Peptides

ABSTRACT

Isolated peptides that are fragments of protein products arising from frameshift mutations in genes associated with cancer are disclosed. The isolated peptides of the invention are capable of eliciting T cell immunity against cells harboring genes with such frameshift mutations. Cancer vaccines and therapeutically effective compositions containing the peptides of the invention are also described.

SUMMARY OF THE INVENTION

This invention relates to peptides which are fragments of proteinproducts arising from frameshift mutations in genes, which peptideselicit T cellular immunity, and to cancer vaccines and compositions foranticancer treatment comprising said peptides.

The invention further relates to a method for identifying such peptideswhich are fragments of protein products arising from frameshiftmutations in genes, which may elicit T cellular immunity which is usefulfor combating cancer associated with said mutated genes.

The invention also relates to DNA sequences encoding at least oneframeshift mutant peptide, and vectors comprising at least one insertionsite containing a DNA sequence encoding at least one frameshift mutantpeptide.

Further the invention relates to methods for the treatment orprophylaxis of cancers associated with frameshift mutations in genes byadministration of at least one frameshift mutant peptide or arecombinant virus vector comprising at least one insertion sitecontaining a DNA sequence encoding at least one frameshift mutantpeptide, or an isolated DNA sequence comprising a DNA sequence encodingat least one frameshift mutant peptide.

The present invention represents a further development of anticancertreatment or prophylaxis based on the use of peptides to generateactivation and strengthening of the anti cancer activity of the Tcellular arm of the body's own immune system.

TECHNICAL BACKGROUND

Tumour Antigens, Status:

T cell defined antigens have now been characterised in a broad spectrumof cancer types. These antigens can be divided into several main groups,depending on their expression. The two main groups are constituted bydevelopmental differentiation related antigens (tumour-testis antigens,oncofoetal antigens etc., such as MAGE antigens and CEA) and tissuespecific differentiation antigens (Tyrosinase, gp100 etc.). The groupcontaining the truly tumour specific antigens contains proteins that arealtered due to mutations in the genes encoding them. In the majority ofthese, the mutations are unique and have been detected in a single or ina small number of tumours. Several of these antigens seem to play a rolein oncogenesis.

Cancer Vaccines, Status:

The focus in cancer vaccine development has been on antigens expressedin a high degree within one form of cancer (such as melanoma) or in manykinds of cancers. One reason for this is the increased recruitment ofpatients into clinical protocols. The field is in rapid growth,illustrated by the accompanying table listing the cancer vaccineprotocols currently registered in the PDQ database of NCI.

Inheritable Cancer/Cancer Gene Testing:

Inherited forms of cancer occur at a certain frequency in thepopulation. For several of these cancer forms, the underlying geneticdefects have been mapped. This is also the case in Lynch syndromecancers which constitute an important group of inheritable cancer. Infamilies inflicted with this syndrome, family members inherit defectgenes encoding DNA Mismatch Repair (MMR) Enzymes. Carriers of such MMRdefects frequently develop colorectal cancer (HNPCC) and other forms ofcancer (list?). Mutations in MMR enzymes can be detected using genetesting in the same way as other cancer related genes can be detected.

Gene testing of risk groups in this case represents an ethical dilemma,since no acceptable forms for prophylactic treatment exist. At presentsurgery to remove the organ in danger to develop cancer has been theonly treatment option. In these patients, cancer vaccines will be a very(interesting) form of prophylaxis, provided efficient vaccines can bedeveloped.

The lack of efficient repair of mismatched DNA results in deletions andinsertions in one strand of DNA, and this happens preferentially instretches of DNA containing repeated units (repeat sequences). Untilnow, focus has been on repeat sequences in the form of non-codingmicrosattelite loci. Indeed microsattelite instability is the hallmarkof cancers resulting from MMR defects. We have taken another approach,and have concentrated on frameshift mutations occurring in DNA sequencescoding for proteins related to the oncogenic process. Such frameshiftmutations result in completely new amino acid sequences in theC-terminal part of the proteins, prematurely terminating where a novelstop codon appears. This results in two important consequences:

1) The truncated protein resulting from the frameshift is generallynonfunctional, in most cases resulting in “knocking out” of an importantcellular function. Aberrant proteins may also gain new functions such asthe capacity to aggragate and form plaques. In both cases the frameshiftresults in disease.

2) The short new C-terminal amino acid sequence resulting from the shiftin the reading frame (the “frameshift sequence”) is foreign to the body.It does not exist prior to the mutation, and it only exists in cellshaving the mutation, i.e. in tumour cells and their pre malignantprogenitors. Since they are completely novel and therefore foreign tothe immune system of the carrier, they may be recognised by T-cells inthe repertoire of the carrier. So far, nobody has focused on this aspectof frameshift mutations, and no reports exist on the characterisation offrameshift peptides from coding regions of proteins as tumour antigens.This concept is therefore novel and forms the basis for developingvaccines based on these sequences. It follows that such vaccines mayalso be used prophyllactively in persons who inherit defective enzymesbelonging to the MMR machinery. Such vaccines will therefore fill anempty space in the therapeutic armament against inherited forms ofcancer.

It has been shown that single amino acid substitutions in intracellular“self”-proteins may give rise to tumour rejection antigens, consistingof peptides differing in their amino acid sequence from the normalpeptide. The T cells which recognise these peptides in the context ofthe major histocompatibility (MHC) molecules on the surface of thetumour cells, are capable of killing the tumour cells and thus rejectingthe tumour from the host.

In contrast to antibodies produced by the B cells, which typicallyrecognise a free antigen in its native conformation and furtherpotentially recognise almost any site exposed on the antigen surface, Tcells recognise an antigen only if the antigen is bound and presented bya MHC molecule. Usually this binding will take place only afterappropriate antigen processing, which comprises a proteolyticfragmentation of the protein, so that the resulting peptide fragmentfits into the groove of the MHC molecule. Thereby T cells are enabled toalso recognise peptides derived from intracellular proteins. T cells canthus recognise aberrant peptides derived from anywhere in the tumourcell, in the context of MHC molecules on the surface of the tumour cell,and can subsequently be activated to eliminate the tumour cellharbouring the aberrant peptide.

M. Barinaga, Science, 257, 880-881, 1992 offers a short review of howMHC binds peptides. A more comprehensive explanation of the TechnicalBackground for this Invention may be found in D. Male et al, AdvancedImmunology, 1987, J.B.lippincott Company, Philadelphia. Both referencesare hereby included in their entirety.

The MHC molecules in humans are normally referred to as HLA (humanleukocyte antigen) molecules. They are encoded by the HLA region on thehuman chromosome No 6.

The HLA molecules appear as two distinct classes depending on whichregion of the chromosome they are encoded by and which T cellsubpopulations they interact with and thereby activate primarily. Theclass I molecules are encoded by the HLA A, B and C subloci and theyprimarily activate CD8+ cytotoxic T cells. The HLA class II moleculesare encoded by the DR, DP and DQ subloci and primarily activate CD4+ Tcells, both helper cells and cytotoxic cells.

Normally every individual has six HLA Class I molecules, usually twofrom each of the three groups A, B and C. Correspondingly, allindividuals have their own selection of HLA Class II molecules, againtwo from each of the three groups DP, DQ and DR. Each of the groups A,B, C and DP, DQ and DR are again divided into several subgroups. In somecases the number of different HLA Class I or II molecules is reduced dueto the overlap of two HLA subgroups.

All the gene products are highly polymorphic. Different individuals thusexpress distinct HLA molecules that differ from those of otherindividuals. This is the basis for the difficulties in finding HLAmatched organ donors in transplantations. The significance of thegenetic variation of the HLA molecules in immunobiology is reflected bytheir role as immune-response genes. Through their peptide bindingcapacity, the presence or absence of certain HLA molecules governs thecapacity of an individual to respond to peptide epitopes. As aconsequence, HLA molecules determine resistance or susceptibility todisease.

T cells may control the development and growth of cancer by a variety ofmechanisms. Cytotoxic T cells, both HLA class I restricted CD8+ and HLAClass II restricted CD4+, may directly kill tumour cells carrying theappropriate tumour antigens. CD4+ helper T cells are needed forcytotoxic CD8+ T cell responses as well as for antibody responses, andfor inducing macrophage and LAK cell killing.

A requirement for both HLA class I and II binding is that the peptidesmust contain a binding motif, which usually is different for differentHLA groups and subgroups. A binding motif is characterised by therequirement for amino acids of a certain type, for instance the onescarrying large and hydrophobic or positively charged side groups, indefinite positions of the peptide so that a narrow fit with the pocketsof the HLA binding groove is achieved. The result of this, takentogether with the peptide length restriction of 8-10 amino acids withinthe binding groove, is that it is quite unlikely that a peptide bindingto one type of HLA class I molecules will also bind to another type.Thus, for example, it may very well be that the peptide binding motiffor the HLA-A1 and HLA-A2 subgroups, which both belong to the class Igender, are as different as the motifs for the HLA-A1 and HLA-B1molecules.

For the same reasons it is not likely that exactly the same sequence ofamino acids will be located in the binding groove of the different classII molecules. In the case of HLA class II molecules the bindingsequences of peptides may be longer, and it has been found that theyusually contain from 10 to 16 amino acids, some of which, at one or bothterminals, are not a part of the binding motif for the HLA groove.

However, an overlap of the different peptide binding motifs of severalHLA class I and class II molecules may occur. Peptides that have anoverlap in the binding sequences for at least two different HLAmolecules are said to contain “nested T cell epitopes”. The variousepitopes contained in a “nested epitope peptide” may be formed byprocessing of the peptide by antigen presenting cells and thereafter bepresented to T cells bound to different HLA molecules. The individualvariety of HLA molecules in humans makes peptides containing nestedepitopes more useful as general vaccines than peptides that are onlycapable of binding to one type of HLA molecule.

Effective vaccination of an individual can only be achieved if at leastone type of HLA class I and/or II molecule in the patient can bind avaccine peptide either in it's full length or as processed and trimmedby the patient's own antigen presenting cells.

The usefulness of a peptide as a general vaccine for the majority of thepopulation increases with the number of different HLA molecules it canbind to, either in its full length or after processing by antigenpresenting cells.

In order to use peptides derived from a protein encoded by a mutatedgene as vaccines or anticancer agents to generate anti tumour CD4+and/or CD8+ T cells, it is necessary to investigate the mutant proteinin question and identify peptides that are capable, eventually afterprocessing to shorter peptides by the antigene presenting cells, tostimulate T cells.

PRIOR ART

In our International Application PCT/NO92/00032 (published asWO92/14756), the content of which is herein incorporated by reference wedescribed synthetic peptides and fragments of oncogene protein productswhich have a point of mutation or translocations as compared to theirproto-oncogene or tumour suppressor gene protein. These peptidescorrespond to, completely cover or are fragments of the processedoncogene protein fragment or tumour suppressor gene fragment aspresented by cancer cells or other antigen presenting cells, and arepresented as a HLA-peptide complex by at least one allele in everyindividual. These peptides were also shown to induce specific T cellresponses to the actual oncogene protein fragment produced by the cellby processing and presented in the HLA molecule. In particular, wedescribed peptides derived from the p21 ras protein which had pointmutations at particular amino acid positions, namely position 12, 13 and61. These peptides have been shown to be effective in regulating thegrowth of cancer cells in vitro. Furthermore, the peptides were shown toelicit CD4+ T cell immunity against cancer cells harbouring the mutatedp21 ras oncogene protein through the administration of such peptides invaccination or cancer therapy schemes. Later we have shown that thesepeptides also elicit CD8+ T cell immunity against cancer cellsharbouring the mutated p21 ras oncogene protein through theadministration mentioned above.

However, the peptides described above will be useful only in certainnumber of cancers, namely those which involve oncogenes with pointmutations or translocation in a proto-oncogene or tumour suppressorgene. There is therefore a strong need for an anticancer treatment orvaccine which will be effective against a more general range of cancers.

In general, tumors are very heterogenous with respect to geneticalterations found in the tumour cells. This implies that both thepotential therapeutic effect and prophylactic strength of a cancervaccine will increase with the number of targets that the vaccine isable to elicit T cell immunity against. A multiple target vaccine willalso reduce the risk of new tumour formation by treatment escapevariants from the primary tumour.

DEFINITION OF PROBLEM SOLVED BY THE INVENTION

There is a continuing need for new anticancer agents based on antigenicpeptides giving rise to specific T cellular responses and toxicityagainst tumours and cancer cells carrying genes with mutations relatedto cancer. The present invention will contribute largely to supply newpeptides that can have a use in the combat and prevention of cancer asingredients in a multiple target anti-cancer vaccine.

Another problem solved by the present invention is that a protection ortreatment can be offered to the individuals belonging to family's orgroups with high risk for hereditary cancers. Hereditary cancers are inmany cases associated with genes susceptible to frameshift mutations asdescribed in this invention (i.e. mutations in mismatch repair genes).Today it is possible to diagnose risk of getting hereditary cancer butno pharmaceutical method for protection against the onset of the canceris available.

DEFINITION OF THE INVENTION

A main object of the invention is to obtain peptides corresponding topeptide fragments of mutant proteins produced by cancer cells which canbe used to stimulate T cells.

Another main object of the invention is to develop a cancer therapy forcancers based on the T cell immunity which may be induced in patients bystimulating their T cells either in vivo or in vitro with the peptidesaccording to the invention.

A third main object of the invention is to develop a vaccine to preventthe establishment of or to eradicate cancers based solely or partly onpeptides corresponding to peptides of the present invention which can beused to generate and activate T cells which produce cytotoxic T cellimmunity against cells harbouring the mutated genes.

A fourth main object of the invention is to design an anticancertreatment or prophylaxis specifically adapted to a human individual inneed of such treatment or prophylaxis, which comprises administering atleast one peptide according to this invention.

These and other objects of the invention are achieved by the attachedclaims.

Since frameshift mutations result in premature stop codons and thereforedeletion in large parts of the proteins, proteins with frameshiftmutations have generally not been considered to be immunogenetic andhave therefore not been considered as targets for immunotherapy. Thus ithas now surprisingly been found that a whole group of new peptidesresulting from frameshift mutations in tumour relevant genes are usefulfor eliciting T cell responses against cancer cells harbouring geneswith such frameshift mutations.

Genes containing a mono nucleoside base repeat sequence of at least fiveresidues, for example of eighth deoxyadenosine bases (AAAAAAAA), or adi-nucleoside base repeat sequence of at least four di-nucleoside baseunits, for example of two deoxyadenosine-deoxycytosine units (ACAC), aresusceptible to frameshift mutations. The frameshift mutations occur,respectively, either by insertion of one or two of the mono-nucleosidebase residue or of one or two of the di-nucleoside base unit in therepeat sequence, or by deletion of one or two of the mono-nucleosidebase residue or of one or two of the di-nucleoside base unit from therepeat sequence. A gene with a frameshift mutation will from the pointof mutation code for a protein with a new and totally different aminoacid sequence as compared to the normal gene product. This mutantprotein with the new amino acid sequence at the carboxy end will bespecific for all cells carrying the modified gene.

In the remainder of this specification and claims the denominationframeshift mutant peptides will comprise such proteins and peptidefragments thereof.

It has now according to the present invention been found that such newprotein sequences arising from frameshift mutations in genes in cancercells give rise to tumour rejection antigens that are recognised by Tcells in the context of HLA molecules.

It has further according to the present invention been found a group ofpeptides corresponding to fragments of mutant proteins arising fromframeshift mutations in genes in cancer cells which can be used togenerate T cells. The said peptides can therefore also be used to rise aT cell activation against cancer cells harbouring a gene with aframeshift mutation as described above.

These peptides are at least 8 amino acids long and correspond, either intheir full length or after processing by antigen presenting cells, tothe mutant gene products or fragments thereof produced by cancer cellsin a human patient afflicted with cancer.

A peptide according to this invention is characterised in that it

a) is at least 8 amino acids long and is a fragment of a mutant proteinarising from a frameshift mutation in a gene of a cancer cell; and

b) consists of at least one amino acid of the mutant part of a proteinsequence encoded by said gene; and

c) comprises 0-10 amino acids from the carboxyl terminus of the normalpart of the protein sequence preceding the amino terminus of the mutantsequence and may further extend to the carboxyl terminus of the mutantpart of the protein as determined by a new stop codon generated by theframeshift mutation in the gene; and

d) induces, either in its full length or after processing by antigenpresenting cell, T cell responses.

The peptides of this invention contain preferably 8-25, 9-20, 9-16, 8-12or 20-25 amino acids. They may for instance contain 9, 12, 13, 16 or 21amino acids.

It is most preferred that the peptides of the present invention are atleast 9 amino acids long, for instance 9-18 amino acids long, but due tothe processing possibility of the antigen presenting cells also longerpeptides are very suitable for the present invention. Thus the wholemutant amino acid sequence may be used as a frameshift mutant peptideaccording to the present invention, if it comprises 8 amino acids ormore.

The invention further relates to a method for vaccination of a persondisposed for cancer, associated with a frameshift mutation in a gene,consisting of administering at least one peptide of the invention one ormore times in an amount sufficient for induction of T-cell immunity tothe mutant proteins encoded by the frameshift mutated gene.

The invention also relates to a method for treatment of a patientafflicted with cancer associated with frameshift mutation in genes,consisting of administering at least one peptide of the invention one ormore times in an amount sufficient for induction of T-cell immunity tomutant proteins arising from frameshift mutations in the genes of cancercells.

Furthermore, it has according to the present invention been found amethod for identifying new peptides which correspond to fragments ofproteins arising from frameshift mutations in genes. This method ischaracterised by the following steps:

1) identifying a gene in a cancer cell susceptible to frameshiftmutation by having a mono nucleoside base repeat sequence of at leastfive residues, or a di-nucleoside base repeat sequence of at least fourdi-nucleoside base units; and

2) removing, respectively, one nucleoside base residue or onedi-nucleoside base unit from the repeat sequence and identifying theamino acid sequence of the protein encoded by the altered gene sequenceas far as to include a new stop codon; and/or

3) removing, respectively, two nucleoside base residues or twodi-nucleoside base units from the repeat sequence and identifying theamino acid sequence of the protein encoded by the altered gene sequenceas far as to include a new stop codon; and/or

4) inserting, respectively, one nucleoside base residue or onedi-nucleoside base unit in the repeat sequence and identifying the aminoacid sequence of the protein encoded by the altered gene sequence as faras to include a new stop codon; and/or

5) inserting, respectively, two nucleoside base residues or twodi-nucleoside base units in the repeat sequence and identifying theamino acid sequence of the protein encoded by the altered gene sequenceas far as to include a new stop codon.

In order to determine whether the peptides thus identified are useablein the compositions and methods according to the present invention forthe treatment or prophylaxis of cancer, the following further stepshould be performed:

6) determining whether the new peptide, either in their full length oras shorter fragments of the peptides, are able to stimulate T cells.

Optionally a further step may be added as follows:

7) determining peptides containing nested epitopes for different majorHLA class I and/or HLA class II molecules.

DETAILED DESCRIPTION OF THE INVENTION

In the present description and claims, the amino acids are representedby their one letter abbreviation as known in the art.

The peptides of the present invention shall be explicitly exemplifiedthrough two different embodiments, wherein cancer develops based onframeshift mutations in specific genes, namely the BAX gene and TGFβRIIgene:

I) BAX Gene

It has been established that the BAX gene is involved in regulation ofsurvival or death of cells by promoting apoptosis. The human BAX genecontains a repeat sequence of eight deoxyguanosine bases (G8) in thethird exon, spanning codons 38 to 41 (ATG GGG GGG GAG).

Frameshift mutations in this G8 repeat have been observed, both as G7(ATG GGG GGG AGG) and G9 (ATG GGG GGG GGA) repeats, both in colon cancercells and prostate cancer cells. The occurency is more than 50% of theexamined cases (Rampino, N. et al., “Somatic frameshift mutations in theBAX gene in colon cancers of the microsatellite mutator phenotype.”,Science (Washington D.C.), 275: 967-969, 1997). The modified BAX geneproducts are unable to promote apoptosis and thus makes further tumourprogress possible. Furthermore the modified gene products are only foundin cancer cells and are therefore targets for specific immunotherapy.

According to the present invention, peptides corresponding to thetransformed BAX protein products arising from frameshift mutations inthe BAX gene can be used as anticancer therapeutical agents or vaccineswith the function to trigger the cellular arm of the immune system(T-cells) against cancer cells in patients afflicted with cancersassociated with a modified BAX gene.

Frameshift mutations in the BAX gene result in mutant peptide sequenceswith the first amino acid of the altered sequence in position 41 ascompared to the normal BAX protein (Table 1, seq.id. no. 1 to 4).

TABLE 1 amino acid pos 41          51        61         71 normal bax EAPELALDPV PQDASTKKLS ECLKRIGDEL peptide; DS . . . seq.id.no. 1 RHPSWPWTRC LRMRPPRS (bax−1G); seq.id.no. 4  GRHPSWPWTR CLRMRPPRS(bax+2G); seq.id.no. 2  GTRAGPGPGA SGCVHQEAER VSQAHRGRTG Q (bax−2G);seq.id.no. 3  GGTRAGPGPG ASGCVHQEAE RVSQAHRGRT GQ (bax+1G);

Table 2 shows one group of peptides according to the present invention:

TABLE 2 seq.id. IQDRAGRMGGRHPSWPWTRCLRMRPPRS no. 5: seq.id.IQDRAGRMGGGRHPSWPWT no. 6: seq.id.IQDRAGRMGGGGTRAGPGPGASGCVHQEAERVSQAHRGRTGQ no. 7: seq.id.IQDRAGRMGGGTRAGPGPG no. 8:

The peptides listed in Table 3 were used for in vitro generation of Tcells that recognise mutant BAX peptides.

TABLE 3 seq id no 1: RHPSWPWTRCLRMRPPRS seq id no 9:IQDRAGRMGGRHPSWPWTRCLR seq id no 6: IQDRAGRMGGGRHPSWPWT seq id no 10:ASGCVRQEAERVSQAHRGRTGQ seq id no 11: GGTRAGPGPGASGCVHQEAERV seq id no12: IQDRAGRMGGGGTRAGPGPGAS seq id no 8: IQDRAGRMGGGTRAGPGPG

The most preferred peptides according to this embodiment of the presentinvention are listed in Table 4:

TABLE 4 seq id RHPSWPWTRCLRMRPPRS no 1: seq idGTRAGPGPGASGCVHQEAERVSQAHRGRTGQ no 2: seq idGGTRAGPGPGASGCVHQEAERVSQAHRGRTGQ no 3: seq id GRHPSWPWTRCLRMRPPRS no 4:seq.id. IQDRAGRMGGRHPSWPWTRCLRMRPPRS no. 5: seq.id. IQDRAGRMGGGRHPSWPWTno. 6: seq.id. IQDRAGRMGGGGTRAGPGPGASGCVHQEAERVSQAHRGRTGQ no. 7: seq idIQDRAGRMGGGTRAGPGPG no 8: seq id IQDRAGRMGGRHPSWPWTRCLR no 9: seq idASGCVHQEAERVSQAHRGRTGQ no 10: seq id GGTRAGPGPGASGCVHQEAERV no 11: seqid IQDRAGRMGGGGTRAGPGPGAS no 12:

2) TGFβRII

It has been established that the TGFβRII gene is involved in regulationof cell growth. TGFβRII is a receptor for TGFβ which down regulates cellgrowth. The human gene coding for TGFβRII contains a repeat sequence often deoxyadenosine bases (A10) from base no. 709 to base no. 718 (GAAAAA AAA AAG CCT). In colon cancers and pancreatic cancers frameshiftmutations in this A10 repeat have been observed, both as A9 (GAA AAA AAAAGC CT) and A11 (GAA AAA AAA AAA GCC) repeats, in approximately 80% ofthe examined cases (Yamamoto, H., “Somatic frameshift mutations in DNAmismatch repair and proapoptosis genes in hereditary nonpolyposiscolorectal cancer.”, Cancer Research 58, 997-1003, Mar. 1, 1998). Themodified TGFβRII gene products are unable to bind TGFβ and the signalfor down regulation of cell growth is eliminated and thus makes furthertumour progress possible. Furthermore the modified gene products areonly found in cancer cells and are therefore targets for immunotherapy.

Consequently peptides corresponding to the transformed TGFβRII proteinproducts arising from frameshift mutations in the TGFβRII gene can beused as anticancer therapeutical agents or vaccines with the function totrigger the cellular arm of the immune system (T-cells) against cancercells in patients afflicted with cancers associated with a modifiedTGFβRII gene.

Frameshift mutations in the TGFβRII gene result in mutant peptidesequences with the first amino acid of the altered sequence in eitherposition 133 (one and two base deletions) or 134 (one and two baseinsertions) as compared to the normal TGFβRII protein (Table 5,seq.id.nos. 13 and 21).

TABLE 5 amino acid 133 pos. normal K PGETFFMCSC SSDECNDNII FSEEYNTSNPTGFβRII; DLLL seq id no S LVRLSSCVPV ALMSAMTTSS SQKNITPAIL TCC 13(−1A);seq id no   SLVRLSSCVP VALMSAMTTS SSQKNITPAI 13(+2A); LTCC TGFbRII +   AW 1A); TGFbRII −  A W 2A);

Table 6 shows one groups of peptides of this invention:

TABLE 6 seq id SPKCIMKEKKSLVRLSSCVPVALMSAMTTSSSQKNITPAILTCC no 14: seqid PKCIMKEKKKSLVRLSSCV no 15: seq id SPKCIMKEKKAW no 19: seq idPKCIMKEKKKAW no 20:

Table 7 presents peptides that were used for in vitro generation of Tcells that recognise mutant TGFβRII peptides.

TABLE 7 seq id no 15: PKCIMKEKKKSLVRLSSCV seq id no 16:ALMSAMTTSSSQKNITPAILTCC seq id no 17: SLVRLSSCVPVALMSAMTTSSSQ seq id no18: SPKCIMKEKKSLVRLSSCVPVA seq id no 19: SPKCIMKEKKAW seq id no 20:PKCIMKEKKKAW seg id no 21: AMTTSSSQKNITPAILTCC seq id no 428: SLVRLSSCV

The most preferred peptides of this embodiment of the present inventionare:

TABLE 8 seq id no 13: SLVRLSSCVPVALMSAMTTSSSQKNITPAILTCC seq id no 14:SPKCIMKEKKSLVRLSSCVPVALMSAMTTSSSQKNITPAILTCC seq id no 15:PKCIMKEKKKSLVRLSSCV seq id no 16: ALMSAMTTSSSQKNITPAILTCC seg id no 17:SLVRLSSCVPVALMSAMTTSSSQ seq id no 18: SPKCIMKEKKSLVRLSSCVPVA seq id no19: SPKCIMKEKKAW seg id no 20: PKCIMKEKKKAW seq id no 21:AMTTSSSQKNITPAILTCC seq id no 428: SLVRLSSCV

Other peptides of the invention can be fragments of the peptides listedin the Tables 1-8 above. Such fragments are most preferred from 9-16amino acids long and include at least one amino acid from the mutantpart of the protein.

As used in this description and claims the term fragment is intended tospecify a shorter part of a longer peptide or of a protein.

Other cancer associated genes containing repeat sequences of anucleoside base and which therefore are susceptible to frameshiftmutations and consequently are potential candidates for peptidesaccording to the present invention (seq id nos according to table 9 aregiven in parentheses in each case) are the following:

Human TGF-β-2 (hTGFβ2) gene (seq id nos 22-29)

Deleted in colorectal cancer (DCC) gene (seq.id.nos. 30-34)

Human breast and ovarian cancer susceptibility (BRCA1) gene (seq.id.nos.378-387)

Human breast cancer susceptibility (BRCA2) gene (seq.id.nos. 35-94)

Human protein tyrosine phosphatase (hPTP) gene (seq.id.nos. 95-102)

Human DNA topoisomerase II (top2) gene (seq.id.nos. 103-108)

Human kinase (TTK) gene (seq.id.nos. 109-120)

Human transcriptional repressor (CTCF) gene (seq.id.nos. 121-127)

Human FADD-homologous ICE/CED-3-like protease gene (seq.id.nos. 128-133)

Human putative mismatch repair/binding protein (hMSH3) gene (seq.id.nos.134-147)

Human retinoblastoma binding protein 1 isoform I (hRBP1) gene(seq.id.nos. 148-156)

Human FMR1 (hFMR1) gene (seq.id.nos. 157-161)

Human TINUR gene (seq.id.nos. 162-169) b-raf oncogene (seq.id.nos.170-175)

Human neurofibromin (NF1) gene (seq.id.nos. 176-181)

Human germline n-myc gene (seq.id.nos. 182-188)

Human n-myc gene (seq.id.nos. 189-194)

Human ras inhibitor gene (seq.id.nos. 195-199)

Human hMSH6 gene (seq.id.nos. 200-203 and 293-297)

Human nasopharynx carcinoma EBV BNLF-1 gene (seq.id.nos. 204-210)

Human cell cycle regulatory protein (E1A-binding protein) p300 gene(seq.id.nos. 211-218)

Human B-cell lymphoma 3-encoded protein (bcl-3) gene (seq.id.nos.219-226)

Human transforming growth factor-beta induced gene product (BIGH3)(seq.id.nos. 227-232)

Human transcription factor ETV1 gene (seq.id.nos. 233-239)

Human insulin-like growth factor binding protein (IGFBP4) gene(seq.id.nos. 240-246)

Human MUC1 gene (seq.id.nos. 247-266)

Human protein-tyrosine kinase (JAK1) gene (seq.id.nos. 267-271)

Human protein-tyrosine kinase (JAK3) gene (seq.id.nos. 272-279)

Human Flt4 gene (for transmembrane tyrosinase kinase) (seq.id.nos.280-284)

Human p53 associated gene (seq.id.nos. 285-292)

Human can (hCAN) gene (seq.id.nos. 298-300)

Human DBL (hDBL) proto-oncogene/Human MCF2PO (hMCF2PO) gene (seq.id.nos.301-306)

Human dek (hDEK) gene (seq.id.nos. 307-309)

Human retinoblastoma related protein (p107) gene (seq.id.nos. 310-313)

Human G protein-coupled receptor (hGPR1) gene (seq.id.nos. 314-319)

Human putative RNA binding protein (hRBP56) gene (seq.id.nos. 320-325)

Human transcription factor (hITF-2) gene (seq.id.nos. 326-327)

Human malignant melanoma metastasis-supressor (hKiSS-1) gene(seq.id.nos. 328-334)

Human telomerase-associated protein TP-1 (hTP-1) gene (seq.id.nos.335-348)

Human FDF-5 (hFDF-5) gene (seq.id.nos. 349-356)

Human metastasis-associated mta1 (hMTA1) gene (seq.id.nos. 357-362)

Human transcription factor TFIIB 90 kDa subunit (hTFIIB90) gene (seq idnos 363-369)

Human tumour suppressor (hLUCA-1) gene (seq id nos 370-377)

Human Wilm's tumour (WIT-1) associated protein (seq id nos 388-393)

Human cysteine protease (ICErel-III) gene (seq id nos 394-398 and 459)

Human Fas ligand (FasL) gene (seq id nos 399-403)

Human BRCA1-associated RING domain protein (BARD1) gene (seq id nos404-417)

Human mcf.2 (hMCF.2) gene (seq id nos 418-422)

Human Fas antigen (fas) gene (seq id nos 423-427)

Human DPC4 gene (seq id nos 429-437).

The mutant peptides that are the results of frameshift mutation in thesegenes, in accordance with the present invention, are listed in table 9.

TABLE 9 seq id no 22; TVGRPHISC seq id no 23; KTVGRPHISC seq id no 24;KQWEDPTSPANVIALLQT seq id no 25; QWEDPTSPANVIALLQT seq id no 26;QKTIKSTRKKTVGRPHISC seq id no 27; QKTIKSTRKKKTVGRPHISC seq id no 28;QKTIRSTRKKKQWEDPTSPANVIALLQT seq id no 29; QKTIKSTRKKQWEDPTSPANVIALLQTseq id no 30; AADLQQQFVHFLDCWDVSSIPFTLHLPQAQDITT seq id no 31; GKDAKEKSSseq id no 32; GKDAKEKKSS seq id no 33;GKDAKEKKAADLQQQFVHFLDCWDVSSIPFTLHLPQAQDITT seq id no 34;GKDAKEKAADLQQQFVHFLDCWDVSSIPFTLHLPQAQDITT seq id no 35; FSMKQTLMKVKNLKTKseq id no 36; KFSMKQTLMNVKNLKTK seq id no 37; VRTSKTRKKFSMKQTLMNVKNLKTKseq id no 38; VRTSKTRKKKFSMKQTLMVKNLKTK seq id no 39; VRTSKTRKKNFP seqid no 40; VRTSKTRKNFP seq id no 41; IKKKLLQFQK seq id no 42; KIKKKLLQFQKseq id no 43; KSRRNYFNFKNNCQSRL seq id no 44; SRRNYFNFKNNCQSRL seq id no45; TNLRVIQKIKKKLLQFQK seq id no 46; TNLRVIQKKIKKKLLQFQK seq id no 47;TNLRVIQKKSRRNYFNFKNNCQSRL seq id no 48; TNLRVIQKSRRNYFNFKNNCQSRL seq idno 49; KIMIT seq id no 50; NIDKIPEKIMIT seq id no 51; NIDKIPEKKIMIT seqid no 52; IINAN seq id no 53; KIINAN seq id no 54; NDKTVSEKIINAN seq idno 55; NDKTVSEKKIINAN seq id no 56; NGLEKEYLMVNQKE seq id no 57;SQTSLLEAKNGLEKEYLMVNQKE seq id no 58; SQTSLLEAKKNCLEKEYLMVNQKE seq id no59; SQTSLLEAKKMA seq id no 60; SQTSLLEAXMA seq id no 61; TLVFPK seq idno 62; KTLVFPK seq id no 63; LKNVEDQKTLVFPK seq id no 64;LKNVEDQKKTLVFPK seq id no 65; LKNVEDQKKH seq id no 66; LKNVEDQKH seq idno 67; KKIQLY seq id no 68; KKKIQLY seq id no 69;RKRFSYTEYLASIIRFIFSVNRRKEIQNLSSCNFKI seq id no 70; LRIVSYSKKKKIQLY seqid no 71; LRIVSYSKKKKKIQLY seq id no 72;LRIVSYSKKRKRFSYTEYLASIIRFIFSVNRRKEIQNLS- SCNFKI seq id no 73;LRIVSYSKRKRFSYTEYLASIIRFIFSVNRRKEIQNLS- SCNFKI seq id no 74;QDLPLSSICQTIVTIYWQ seq id no 75; KQDLPLSSICQTIVTIYWQ seq id no 76;NRTCPFRLFVPRILQFTCNKVLDRP seq id no 77; GFWSVVKKQDLPLSSICQTIVTIYWQ seqid no 78; GFVVSWKKKQDLPLSSICQTIVTIYWQ seq id no 79;GFVVSWKKNRTCPFRLFVRRMLQFTGNKVLDRP seq id no 80;GFVVSVVKNRTCPFRLFVRRMLQFTGNKVLDRP seq id no 81; YRKTKNQN seq id no 82;KYRKTKNQN seq id no 83; NTERPKIRTN seq id no 84; DETFYKGKKYRKTKNQN seqid no 85; DETFYKGKKKYRKTKNQN seq id no 86; DETFYKGKKNTERPKIRTN seq id no87; DETFYKGKNTERPKIRTN seq id no 88; LSINNYRFQMKFYFRFTSHGSPFTSANF seq idno 89; KLSINNYRFQMKFYFRFTSHGSPFTSANF seq id no 90; NSVSTTTGFR seq id no91; NIQLAATKKLSINNYRFQMKFYFRFTSHGSPFTSANF seq id no 92;NIQLAATKKKLSINNYRFQMKFYFRFTSHGSPFTSANF seq id no 93; NIQLAATKKNSVSTTTGFRseq id no 94; NIQLAATKNSVSTTTGFR seq id no 95; MEHVAPGRMSASPQSPTQ seq idno 96; KMEHVAPGRMSASPQSPTQ seq id no 97;KWSTWLQAECQHLHSPQRSDKPQQAGLDQQHHCFALDS- SPGPRPVFLQLLGLMGQGRHD seq id no98; WSTWLQAECQRLHSPQRSDKPQQAGLDQQHHCFALDSS- PGPRPVFLQLLGLMGQGRHD seq idno 99; TFSVWAEKMEHVAPGRMSASPQSPTQ seq id no 100;TFSVWAEKKMEHVAPGRMSASPQSPTQ seq id no 101;TFSVWAEKKWSTWLQAECQHLHSPQRSDKPQQAGLDQ- QHHCFALDSSPGPRPVFLQLLGLMGQGRHDseq id no 102; TFSVWAEKWSTWLQAECQHLHSPQRSDKPQQAGLDQ-QHHCFALDSSPGPRPVFLQLLGLMGQGRHD seq id no 103; HKWLKFCLLRLVKESFHE seq idno 104; KHKWLKFCLLRLVKESFHE seq id no 105; KGGKAKGKKHKWLKFCLLRLVKESFHEseq id no 106; KGGKAKGKKKHKWLKFCLLRLVKESFHE seq id no 107; KGGKAKGKKNTNGseq id no 108; KGGKAKGKNTNG seq id no 109; VNNFFKKL seq id no 110;KVNNFFKKL seq id no 111; LSQGNVKKVNNFFKKL seq id no 112;LSQGNVKKKVNNFFKKL seq id no 113; GEKNDLQLFVMSDRRYKIYWTVILLNPCGNLHLKTTSLseq id no 114; KGEKNDLQLFVMSDRRYKIYWTVILLNPCGNLHLKTTSL seq id no 115;KGKKMICSYS seq id no 116; GKKMICSYS seq id no 117;SSKTFEKKGEKNDLQLFVMSDRRYKIYWTVILLNPCGN- LHLKTTSL seq id no 118;SSKTFEKKKGEKNDLQLFVMSDRRYKIYWTVILLNPCGN- LHLKTTSL seq id no 119;SSKTFEKKKGKKMICSYS seq id no 120; SSKTFEKKCKKMICSYS seq id no 121;QRKPKRANCVIQRRAKM seq id no 122; KQRKPKRANCVIQRRAKM seq id no 123;NKENQKEQTALLYRGGQRCRCVCLRF seq id no 123; NKENQKEQTALLYRGGQRCRCVCLRF seqid no 124; PDYQPPAKKQRXPKRANCVIQRRAKM seq id no 125;PDYQPPAKKKQRKPKRANCVIQRRAKM seq id no 126;PDYQPPAKKNKENQKEQTALLYRCGQRCRCVCLRF seq id no 127;PDYQPPAKNKENQKEQTALLYRGGQRCRCVCLRF seq id no 128; NLSSLLI seq id no 129;TCLPF seq id no 130; QPTFTLRKNLSSLLI seq id no 131; QPTFTLRKKNLSSLLI seqid no 132; QPTFTLRKKTCLPF seq id no 133; QPTFTLRKTCLPF seq id no 134;RATFLLSLWECSLPQARLCLIVSRTGLLVQS seq id no 135; GQHFYWHCGSAACHRRGCV seqid no 136; KENVRDKKRATFLLSLWECSLPQARLCLIVSRTGLLVQS seq id no 137;KENVRDKKKRATFLLSLWECSLPQARLCLIVSRTGLLVQS seq id no 138;KENVRDKKKGQHFYWHCGSAACHRRGCV seq id no 139; KENVRDKKGQHFYWHCGSAACHRRGCVseq id no 140; ITHTRWGITTWDSWSVRMKANWIQAQQNKSLILSPSFTK seq id no 141;KITHTRWGITTWDSWSVRRKANWIQAQQNKSLILSPSFTK seq id no 142; KLLTPGGELPHGILGQseq id no 143; LLTPGGELPHGILCQ seq id no 144;PPVCELEKITHTRWGITTWDSWSVRMKANWIQAQQNKS- LILSPSFTK seq id no 145;PPVCELEKKITHTRWGITTWDSWSVRMKANWIQAQQNKS- LILSPSFTK seq id no 146;PPVCELEKKLLTPGGELPHGILGQ seq id no 147; PPVCELEKLLTPGGELPHGILGQ seq idno 148; SLKDELEKMKI seq id no 149; SLKDELEKKMKI seq id no 150;LGQSSPEKKNKN seq id no 151; LGQSSPEKNKN seq id no 152;RLRRINGRGSQIRSRNAFNRSEE seq id no 153; EPKVKEEKKT seq id no 154;EPKVKEEKKKT seq id no 155; EPKVKEEKKRLRRINGRGSQIRSRNAFNRSEE seq id no156; EPKVKEEKRLRRINGRGSQIRSRNAFNRSEE seq id no 157; TFRYKGKQHPFFST seqid no 158; GPNAPEEKNH seq id no 159; GPNAPEEKKNH seq id no 160;GPNAPEEKKTFRYKGKQHPFFST seq id no 161; GPNAPEEKTFRYKGKQHPFFST seq id no162; MQNTCV seq id no 163; KMQNTCV seq id no 164; KCKIRVFSK seq id no165; CKIRVFSK seq id no 166; FFKRTVQKMQNTCV seq id no 167;FFKRTVQKKMQNTCV seq id no 168; FFKRTVQKKCKIRVFSK seq id no 169;FFKRTVQKCKIRVFSK seq id no 170; LPHYLAH seq id no 171; CLITWLTN seq idno 172; GSTTGLSATPLPHYLAH seq id no 173; GSTTGLSATPPLPHYLAH seq id no174; GSTTGLSATPPCLITWLTN seq id no 175; GSTTGLSATPCLITWLTN seq id no176; RFADKPRPN seq id no 177; DLPTSPDQTRSGPVHVSVEP seq id no 178;DSAAGCSGTPRFADKPRPN seq id no 179; DSAAGCSGTPPRFADKPRPN seq id no 180;DSAAGCSGTPPDLPTSPDQTRSGPVHVSVEP seq id no 181;DSAAGCSGTPDLPTSPDQTRSGPVHVSVEP seq id no 182;AHPETPAQNRLRIPCSRREVRSRACKPPGAQGSDER- RGKASPGRDCDVRTGRP seq id no 183;PAHPETPAQNRLRIPCSRREVRSRACKPPGAQGSDER- RGKASPGRDCDVRTGRP seq id no 184;RPTRRHPRRIASGSPAVGGR seq id no 185;VAIRGHPRPPAHPETPAQNRLRIPCSRREVRSRACKP- PGAQGSDERRGKASPGRDCDVRTGRP seq idno 186; VAIRGHPRPPPAHPETPAQNRLRIPCSRREVRSRACKP-PGAQGSDERRGKASPGRDCDVRTGRP seq id no 187; VAIRGHPRPPRPTRRHPRRIASGSPAVGGRseq id no 188; VAIRGHPRPRPTRRHPRRIASGSPAVGGR seq id no 189;RGRTSGRSLSCCRRPRCRPAVASRSTAPSPRAGSR- RCCLRTSCGAARPRRTRSACGDWVASPPTRSS-SRTACGAASPPARSWSAP seq id no 190; GGGHLEEV seq id no 191;YFGGPDSTPRGRTSGRSLSCCRRPRCRPAVASR- STAPSPRAGSRRCCLRTSCGAARPRRTRSACGD-WVASPPTRSSSRTACGAASPPARSWSAP seq id no 192;YFGGPDSTPPRGRTSGRSLSCCRRPRCRPAVASR- STAPSPRAGSRRCCLRTSCGAARPRRTRSACGDW-VASPPTRSSSRTACGAASPPARSWSAP seq id no 193; YFGGPDSTPPGGGHLEEV seq id no194; YFGGPDSTPGGGHLEEV seq id no 195; HRVADP seq id no 196;LSQSSELDPPSSR seq id no 197; LSQSSELDPPPSSR seq id no 198;LSQSSELDPPHRVADP seq id no 199; LSQSSELDPHRVADP seq id no 200;VILLPEDTPPS seq id no 201; VILLPEDTPPPS seq id no 202; VILLPEDTPPLLRAseq id no 203; VILLPELDPLLRA seq id no 204; PSPLP seq id no 205;PLLFHRPCSPSPALGATVLAVYRYE seq id no 206; LLFHRPCSPSPALGATVLAVYRYE seq idno 207; APRPPLGPPSPLP seq id no 208; APRPPLGPPPSPLP seq id no 209;APRPPLGPPPLLFHRPCSPSPALGATVLAVYRYE seq id no 210;APRPPLGPPLLFHRPCSPSPALGATVLAVYRYE seq id no 211;TQVLPQGCSLSLLHTTFPHRQVPHILDW seq id no 212;PTQVLPQGCSLSLLHTTFPHRQVPHILDW seq id no 213;PLQSFPKDAASAFSTPRFPTDKFPTSWTGSCPGQPHGT- RAFCQPGPEFNAFSAC seq id no 214;LQSFPKDAASAFSTPRFPTDKFPTSWTGSCPGQPHGT- RAFCQPGPEFNAFSAC seq id no 215;PSPRPQSQPPTQVLPQGCSLSLLHTTFPHRQVPHILDW seq id no 216;PSPRPQSQPPPTQVLPQGCSLSLLHTTFPHRQVPHILDW seq id no 217;PSPRPQSQPPPLQSFPKDAASAFSTPRFPTDKFPTS- WTGSCPGQPHGTRAFCQPGPEFNAFSAC seqid no 218; PSPRPQSQPPLQSFPKDAASAFSTPRFPTDKFPTS-WTGSCPGQPHGTRAFCQPGPEFNAFSAC seq id no 219;TAWPGRRRFTTPEPYCLCTPLGPWAPRFLW seq id no 220;PTAWPGRRRFTTPEPYCLCTPLGPWAPRFLW seq id no 221;PRPGPAGGALLPRSLTAFVPHSGHGLPVSSGEPAYTPIP- HDVPHGTPPFC seq id no 222;RPGPAGGALLPRSLTAFVPHSGHGLPVSSGEPAYTPIPH- DVPHGTPPFC seq id no 223;DLPAVPGPPTAWPGRRRFTTPEPYCLCTPLGPWAPRFLW seq id no 224;DLPAVPGPPPTAWPGRRRFTTPEPYCLCTPLGPWAPRFLW seq id no 225;DLPAVPGPPPRPGPAGGALLPRSLTAFVPHSGHGLPVSSG- EPAYTPIPHDVPHGTPPFC seq id no226; DLPAVPGPPRPGPAGGALLPRSLTAFVPHSGMGLPVSSG- EPAYTPIPHDVPHGTPPFC seq idno 227; QWCLSWMS seq id no 228; NGDCHGCPEGRQSL seq id no 229;FTMDRVLTPQWGLSWMS seq id no 230; FTMDRVLTPPQWGLSWMS seq id no 231;FTMDRVLTPPNGDCHGCPEGRQSL seq id no 232; FTMDRVLTPNGDCHGCPEGRQSL seq idno 233; HHPARQCPHCIMHLQTQLIHRNLTGPSQLTSLHRS-PYQIAATPWTTDFAASFFLNPVTPFLLCRRCQGKDV- LCTNARCLSQTSPSHHKALSRTTTQCMNT-TPWLAVRPAKAFPLL seq id no 234; PHHPARQCPHCIMHLQTQLIHRNLTGPSQLTSLHRS-PYQIAATPWTTDFAASFFLNPVTPFLLCRRCQGK- DVLCTNARCLSQTSPSHHKALSRTTTQCMNTTP-WLAVRPAKAFPLL seq id no 235; HTIQHASVPTASCISKLNSYTEN seq id no 236;PQVGMRPSNPPHHPARQCPHCIMHLQTQLIHRNLT-GPSQLTSLHRSPYQIAATPWTTDFAASFFLNPVTPFL-LCRRCQGKDVLCTNARCLSQTSPSHHKALSRTTTQC- MNTTPWLAVRPAKAFPLL seq id no 237;PQVGMRPSNPPPHHPARQCPHCIMHLQTQLIHRNLTGPS-QLTSLHRSPYQIAATPWTTDFAASFFLNPVTPFLLCRRC-QGKDVLCTNARCLSQTSPSHHKALSRTTTQCMNTTPWLA- VRPAKAFPLL seq id no 238;PQVGMRPSNPPHTIQHASVPTASCISKLNSYTEN seq id no 239;PQVGMRPSNPHTIQHASVPTASCISKLNSYTEN seq id no 240;WAARSWCERAAAAVAPLAPWAWGCPAGCTPPVAARAC- AATRPEGWRSPCTH seq id no 241;PWAARSWCERRAAAVAPLAPWAWGCPAGCTPPVAA- RACAATRPEGWRSPCTH seq id no 242;RGLRGAGARGGLRLLRHLRPGLGDALRGVHPPLR-LGPALLPAPRGGEAPAHTDARARRVHGAGGDRGHPGPAAL seq id no 243;EEKLARCRPPWAARSWCERRAAAVAPLAPWAWGCPAGC- TPPVAARACAATRPEGWRSPCTH seq idno 244; EEKLARCRPPPWAARSWCERRAAAVAPLAPWAWGCPA- GCTPPVAARACAATRPEGWRSPCTHseq id no 245; EEKLARCRPPRGLRGAGARGGLRLLRHLRPGLGDA-LRGVHPPLRLGPALLPAPRGGEAPAHTDARARRVHGAGG- DRGHPGPAAL seq id no 246;EEKLARCRPRGLRGAGARGGLRLLRHLRPGLGDALRG-VHPPLRLGPALLPAPRGGEAPAHTDARARRVHGAGG- DRGHPGPAAL seq id no 247;QPPVSPRPRRPGRPRAPPPPQPMVSPRRRTTGPPW-RPPPLQSTMSPPPQALHQAQLLLWCTTAPLPGLPQPQ-PARALHSQFPATTLILLPPLPAIAPRLMPVALTIARYL-LSPPPITALLPSCLLGSLSFSCLFTFQTSSLIPLW- KIPAPTTTKSCRETFLKW seq id no 248;SPGCHLGPGDQAAPGLHRPPSPWCHLGAGQQARLGVHR-PSSPQCHLGLRLCIRLSFYSGAQRHLCQGYHNPSQQEHS ILNSQPPL seq id no 249;KPAPGSTAPQPPVSPRPRRPGRPRAPPPPQPMVSPRR-RTTGPPWRPPPLQSTMSPPPQALHQAQLLLWCTTAP-LPGLPQPQPARALHSQFPATTLILLPPLPAIAPRLMPVA-LTIARYLLSPPPITALLPSCLLGSLSFSCLFTFQTS- SLIPLWKIPAPTTTKSCRETFLKW seq id no250; KPAPGSTAPPQPPVSPRPRRPGRPRAPPPPQPMVSPR-RRTTGPPWRPPPLQSTMSPPPQALHQAQLLLWCT-TAPLPGLPQPQPARALHSQFPATTLILLPPLPAIAP-RLMPVALTIARYLLSPPPITALLPSCLLGSLSFSCLF- TFQTSSLIPLWKIPAPTTTKSCRETFLKW seqid no 251; KPAPGSTAPPSPGCHLGPGDQAAPGLHRPPSPWCHL-GAGQQARLGVHRPSSPQCHLGLRLCIRLSFYSGA- QRHLCQGYHNPSQQEHSILNSQPPL seq id no252; KPAPGSTAPSPGCHLGPGDQAAPGLHRPPSPWCHL-GAGQQARLGVHRPSSPQCHLGLRLCIRLSFYSGAQ- RHLCQGYHNPSQQEHSILNSQPPL seq id no253; QPMVSPRRRTTGPPWRPPPLQSTMSPPPQALHQAQL-LLWCTTAPLPGLPQPQPARALHSQFPATTLILLPPLP-AIAPRLMPVALTIARYLLSPPPITALLPSCLLGSL- SFSCLFTFQTSSLIPLWKIPAPTTTKSCRETFLKWseq id no 254; SPWCHLGAGQQARLGVHRPSSPQCHLGLRLCIRLSF-YSGAQRHLCQGYHNPSQQEHSILNSQPPL seq id no 255; RPPPGSTAPQPMVSPRRR seq idno 256; RPPPGSTAPPQPMVSPRRR seq id no 257; RPPPGSTAPPSPWCHLGA seq id no258; RPPPGSTAPSPWCHLGA seq id no 259; RPRAPPPPSPWCHL seq id no 260;RPRAPPPPPSPWC seq id no 261; RPRAPPPPAHGVTSAP seq id no 262;RPRAPPPPPAHGV seq id no 263; APGLHRPPQPMVSP seq id no 264;AAPGLHRPQPMVSPR seq id no 265; PGLHRPPPAHGVT seq id no 266;APGLHRPPAHGVTS seq id no 267; VDRPQHTEWLSWSNLYRIRHQ seq id no 268;HYLCTDVAPR seq id no 269; HYLCTDVAPPR seq id no 270;HYLCTDVAPPVDRPQHTEWLSWSNLYRIRHQ seq id no 271;HYLCTDVAPVDRPQHTEWLSWSNLYRIRHQ seq id no 272;SAYLSPLCTTWLRTCACRLPRPAASCLCTTPSLLW- PRRTCPAGSPRATSSPWRMPAPKSCCTTCLAFTS-PIGLGWRSATASGYARIWPVLSLTCQSWSTSLPSTAVTW seq id no 273;PSAYLSPLGTTWLRTCACRLPRPAASCLCTTPSLLWP-RRTCPACSPRATSSPWRMPAPKSCCTTCLAFTSP-IGLGWRSATASGYARIWPVLSLTCQSWSTSLPSTAVTW seq id no 274; PAPIFLLWGPLG seqid no 275; APIFLLWGPLC seq id no 276;LPARAPGPPSAYLSPLGTTWLRTCACRLPRPAASCL-CTTPSLLWPRRTCPACSPRATSSPWRMPAPKSCC- TTGLAFTSPIGLGWRSATASGYARIWPVLSLT-CQSWSTSLPSTAVTW seq id no 277; LPARAPGPPPSAYLSPLGTTWLRTCACRLPRPAAS-CLCTTPSLLWPRRTCPAGSPRATSSPWRMPAPKSCC- TTGLAFTSPIGLGWRSATASGYARIWPVLSLTC-QSWSTSLPSTAVTW seq id no 278; LPARAPGPPPAPIFLLWGPLG seq id no 279;LPARAPGPPAPIFLLWGPLG seq id no 280; DLEHHCGVTRHRHR seq id no 281;LVSDYSMTPRP seq id no 282; LVSDYSMTPPRP seq id no 283;LVSDYSMTPPDLEHHCGVTRHRHR seq id no 284; LVSDYSMTPDLEHHGGVTRHRHR seq idno 285; FHHIATDVGPFVRIGFLKIKGKIKGKSLRKPNW- KTQHKLKRALMFLIVKKL seq id no286; PFHHIATDVGPFVRIGFLKIKGKIKGKSLRKPNWK- TQHKLKRALMFLIVKKL seq id no287; PSITLQQMLAPS seq id no 288; SITLQQMLAPS seq id no 289;TSCNEMNPPFHHIATDVGPFVRIGFLKIKGKIKGKSL- RKPNWKTQHKLKRALMFLIVKKL seq id no290; TSCNEMNPPPFHHIATDVGPFVRIGFLKIKGKIKG- KSLRKPNWKTQHKLKRALMFLIVKKL seqid no 291; TSCNEMNPPSITLQQMLAPS seq id no 292; TSCNEMNPPPSITLQQMLAPS seqid no 293; LEMILFLMTF seq id no 294; HPCITKTFLEMILFLMTF seq id no 295;HPCITKTFFLEMILFLMTF seq id no 296; HPCITKTFFWR seq id no 297; HPCITKTFWRseq id no 298; LMFEHSQMRLNSKNAHLPIISF seq id no 299;EYGSIIAFLMFERSQMRLNSKNAHLPIISF seq id no 300:EYGSIIAFFLMFEHSQMRLNSKNAHLPIISF seq id no 301: HLNKGRRLGDKIRAT seq id no302; FHLNKGRRLGDKIRAT seq id no 303; VTSGTPFFHLNKGRRLGDKIRAT seq id no304; VTSGTPFFFHLNKGRRLGDKIRAT seq id no 305; VTSGTPFFFI seq id no 306;VTSGTPFFI seq id no 307; CEIERIHFFF seq id no 308; CEIERIHFFSK seq id no309; CEIERIHFSK seq id no 310; FRYISKSI seq id no 311; RYISKSI seq id no312; FKKYEPIFFRYISKSI seq id no 313; FKKYEPIFRYISKSI seq id no 314;FPDSDQPGPLYPLDPSCLISSASNPQELSDCHYIH- LAFGFSNWRSCPVLPGHCGVQ seq id no315; PDSDQPGPLYPLDPSCLISSASNPQELSDCHYIHL- AFGFSNWRSCPVLPGHCGVQ seq id no316; LNMFASVFS seq id no 317; LNMFASVFFS seq id no 318;LNMFASVFFPDSDQPGPLYPLDPSCLISSASNPQE- LSDCHYIHLAFGFSNWRSCPVLPGHCGVQ seqid no 319; LNMFASVFPDSDQPGPLYPLDPSCLISSASNPQELS-DCHYIHLAFGFSNWRSCPVLPGHCGVQ seq id no 320;AMEETVVVAVATVETEVEAMEETGVVAAMEETEVGAT- EETEVAMEAKWEEETTTEMISATDHT seq idno 321; LWVRPWLWEWLRWRPKWRLWRRQEWWRLWRRPRWGL- RRRPRWLWRENGRKKRLQK seq idno 322; YGGDRSRGAMEETVVVAVATVETEVEAMEETGVVAAM-EETEVGATEETEVAMEAKWEEETTTEMISATDHT seq id no 323;YGGDRSRGGAMEETVVVAVATVETEVEAMEETGVVA-AMEETEVGATEETEVAMEAKWEEETTTEMISATDHT seq id no 324;YGGDRSRGGLWVRPWLWEWLRWEPKWRLWRRQEWW- RLWRRPRWGLRRRPRWLWRENGRKKRLQK seqid no 325; YGGDRSRGLWVRPWLWEWLRWEPKWRLWRRQEWWR-LWRRPRWGLRRRPRWLWRENGRKKRLQK seq id no 326; EFGGGRRQK seq id no 327;EFGGRRQK seq id no 328; RRAKGGGAGASNPRQ seq id no 329; GRRAKGGGAGASNPRQseq id no 330; DVGLREGALELPTRGNKRNVA seq id no 331;MRGGGGVGGRRAKGGGAGASNPRQ seq id no 332; MRGGGGVGGGRRAKGGGAGASNPRQ seq idno 333; MRGGGGVGGDVGLREGALELPTRGNKRNVA seq id no 334;MRGGGGVGDVGLREGALELPTRGNKRNVA seq id no 335; VWQLAGPMLAGWRSLGSWFCRMYGIseq id no 336; CGSWPALCWRAGGVWAVGSAGCMEYDPEALPAAWGP- AAAATVHPRR seq idno 337; RRYPCEWGVWQLAGPMLAGWRSLGSWFCRMYGI seq id no 338;RRYPCEWGGVWQLAGPMLAGWRSLGSWFCRMYGI seq id no 339;RRYPCEWGGCGSWPALCWRAGGVWAVGSAGCMEYD- EALPAAWGPAAAATVHPRR seq id no 340;RRYPCEWGCGSWPALCWRAGGVWAVGSAGCMEYDPE- ALPAAWGPAAAAIVHPRR seq id no 341;LWLWAGWTVWWSCGPGEKGHGWPSLPTMALLLLRFSCM- RVASY seq id no 342;GLWLWAGWTVWWSCGPGEKGHGWPSLPTMALLLL- RFSCMRVASY seq id no 343;GCGCGPAGQYGGAVGLARRGTAGCLPCPPWLCCCCAF-PACGLPGTDGWRGWQGSGCVRVSGSAPWAPGFPFSP- PCPLCGTQPRW seq id no 344;CGCGPAGQYGGAVGLARRGTAGCLPCPPWLCCCCAFPACG-LPGTDGWRGWQGSGCVRVSGSAPWAPGFPFSPPC- PLCGTQPRW seq id no 345;LAFNVPGGLWLWAGWTVWWSCGPGEKGHGWPSLPTMA- LLLLRFSCMRVASY seq id no 346;LAFNVPGGGLWLWAGWTVWWSCGPGEKGHGWPSLPTM- ALLLLRFSCMRVASY seq id no 347;LAFNVPGGCCGCGPAGQYCGAVGLARRGTACCLPCPP-WLCCCCAFPACGLPGTDGWRGWQGSGCVRVSGSAPW- APGFPFSPPCFLCGTQPRW seq id no 348;LAFNVPGGCGCGPAGQYGGAVGLARRGTAGCLPCPPW-LCCCCAFPACGLPGTDGWRGWQGSGCVRVSGSAPWA- PGFPFSPPCPLCGTQPRW seq id no 349;PPMPMPGQREAPGRQEA seq id no 350; GPFMPMPGQREAPGRQEA seq id no 351;GHQCQCQGKGRHRADRRPDTAQEE seq id no 352; HQCQCQGKGRHRADRRPDTAQEE seq idno 353; GGHSYGGGPPMPMPGQREAPGRQEA seq id no 354;GGHSYGGGGPPMPMPGQREAPGRQEA seq id no 355;GGHSYGGGGHQCQCQGKGRHRADRRPDTAQEE seq id no 356;GGHSYGGGHQCQCQGKGRHRADRRPDTAQEE seq id no 357; APCPQSSGGG seq id no 358;LPAPSQAAADELDRRPG seq id no 359; TKVRLIRGAPCPQSSGGG seq id no 360;TKVRLIRGGAPCPQSSGGG seq id no 36l; TKVRLIRGGLPAPSQAAADELDRRPG seq id no362; TKVRLIRGLPAPSQAAADELDRRPG seq id no 363;CSLAKDGSTEDTVSSLCGEEDTEDEELEAAASHLNK- DLYRELLGG seq id no 364;GCSLAKDGSTEDTVSSLCGEEDTEDEELEAAASHLNK- DLYRELLGG seq id no 365;AAAWQKMAPPRTPRPACVARR seq id no 366;ENSRPKRGGCSLAKDGSTEDTVSSLCGEEDTEDEELE- AAASHLNKDLYRELLGG seq id no 367;ENSRPKRGGGCSLAKDGSTEDTVSSLCGEEDTEDE- ELEAAASHLNKDLYRELLGG seq id no 368;ENSRPKRGGAAAWQKMAPPRTPRPACVARR seq id no 369;ENSRPKRGAAAWQKMAPPRTPRPACVARR seq id no 370; HCVLAASGAS seq id no 371;GHCVLAASGAS seq id no 372; GTASSRPLGLPKPHLHRPVPIRHPSCPK seq id no 373;TASSRPLGLPKPHLHRPVPIRHPSCPK seq id no 374; AGTLQLGGHCVLAASGAS seq id no375; AGTLQLGGGHCVLAASGAS seq id no 376;AGTLQLGGGTASSRPLGLPKPHLHRPVPIRHPSCPK seq id no 377;AGTLQLGGTASSRPLGLPKPHLHRPVPIRHPSCPK seq id no 378; RRTPSTEKR seq id no379; RRTPSTEKKR seq id no 380; RRTPSTEKKGRSEC seq id.no 381;RRTPSTEKGRSEC seq id no 382; STTKCQSGTAETYNSWKVKNLQLEPRRVTSQMNRQVK-DMTAILSQS seq id no 384; SSEEIKKKSTTKCQSGTAETYNSWKVKNLQLEPRRV-TSQMNRQVKDMTAILSQS seq id no 385; SSEEIKKKKSTTKCQSGTAETYNSWKVKNLQLEPRR-VTSQMNRQVKDMTAILSQS seq id no 386; SSEEIKKKKVQPNASQAQQKPTTHGR seq id no387; SSEEIKKKVQPNASQAQQKPTTHGR seq.id no 388; NRGWVGAGE seq id no 389;IEAG seq id no 390; VHNYCNMKNRGWVGAGE seq id no 391; VHNYCNMKKNRGWVGAGEseq id no 392; VHNYCNMKKIEAG seq id no 393; VHNYCNMKIEAG seq id no 394;QLRCWNTWAKMFFMVFLIIWQNTMF seq id no 395;VKKDWHKKQLRCWNTWAKMFFMVFLIIWQNTMF seq id no 396;VKKDNHKKKQLRCWNTWAKMFFMVFLIIWQNTMF seq id no 397; VKKDNHKKKNS seq id no398; VKKDNHKKNS seq id no 399; GAEESGPFNRQVQLKVHASGMGRHLWNCPAFWSEV seqid no 400; IIPSPPPEKRS seq id no 401; HPSPPPEKKRS seq id no 402;HPSPPPEKKGAEESGPFNRQVQLKVHASGMGRHLW- NCPAFWSEV seq id no 403;HPSPPPEKGAEESGPFNRQVQLKVHASGMGRHLWN- CPAFWSEV seq id no 404;MQVLSKTHMNLFPQVLLQMFLRGLKRLLQDLEKSKKRKL seq id no 405; RCKSARLI seq idno 406; VQTQPAIKKMQVLSKTHMNLFPQVLLQMFLRGLKRLLQ- DLEKSKKRKL seq id no407; VQTQPAIKKKMQVLSKTHMNLFPQVLLQMFLRGLKRL- LQDLEKSKKRKL seq id no 408;VQTQPAIKKRCKSARLI seq id no 409; VQTQPAIKRCKSARLI seq id no 410;ARSGKKQKRKL seq id no 411; ARSGKKQKKRKL seq id no 412; ARSGKKQKKENFS seqid no 413; ARSGKKQKENFS seq id no 414; KASARSGKSKKRKL seq id no 415;KASARSGKKSKKRKL seq id no 416; KASARSGKKAKKENSF seq id no 417;KASARSGKAKKENSF seq id no 418; HLNKGRRLGDKIRAT seq id no 419;VTSGTPFFHLNKGRRLGDKIRAT seq id no 420; VTSGTPFFFHLNKGRRLGDKIRAT seq idno 421; VTSGTPFFFI seq id no 422; VTSGTPFFI seq id no 423;VTLLYVNTVTLAPNVNMESSRNAHSPATPSAKRK- DPDLTWGGFVFFFCQFH seq id no 424;KCRCKPNFFVTLLYVNTVTLAPNVNMESSRNAHSP- ATPSAKRKDPDLTWGGFVFFFCQFH seq id no425; KCRCKPNFFFVTLLYVNTVTLAPNVNMESSRNAH- SPATPSAKRKDPDLTWGGFVFFFCQFH seqid no 426; KCRCKPNFFL seq id no 427; KCRCKPNFL seq id no 429;LVKKLKEKKMNWIL seq id no 430; LVKKLKEKKKNNWIL seq id no 431; LVKKLKEKKRseq id no 432; LVKKLKEKR seq id no 433; AAIVKDCCR seq id no 434;SQPASILGRKL seq id no 435; SQPASILGKRKL SQPASILGKAAIVKDCCR seq id no436; SQPASILGKAAIVKDCCR seq id no 437; SQPASILGAAIVKDCCR seq id no 459;NTWAKMFFMVFLIIWQNTMF

Examples of cancers particularly suitable for treatment with one or acombination of several of this compounds are: colorectal cancer, breastcancer, small-cell lung cancer, non small-cell lung cancer, liver cancer(primary and secondary), renal cancer, melanoma, ovarian cancer, cancerof the brain, head and neck cancer, pancreatic cancer, gastric cancer,eosophageal cancer, prostate cancer and leukemias and lymphomas.

Below are listed some examples of where these mutations may result ingene products that result in development of tumours:

Development of colorectal cancers are believed to result from a seriesof genetic alterations. Deleted in colorectal cancer (DCC) gene (seq idnos 30-34), Human cysteine protease (ICErel-III) gene (seq id nos394-398 and 459), Human putative mismatch repair/binding protein (hMSH3)gene (Seq id nos 134-147), Human hMSH6 gene (seq id nos 200-203 and293-297), Human n-myc gene (seq id nos 189-194), Human TGFβ2 (hTGFβ2)gene (seq id nos 22-29), Human p53 associated gene (seq id nos 285-292)may be involved in colorectal cancer.

Human breast cancer susceptibility (BRCA2) (seq id nos 35-94) and HumanBRCA1-associated RING domain protein (BARD1) gene (seq id nos 404-417)are involved in breast cancer and ovarian cancer Human hMSH6 gene (seqid nos 200-203 and 293-297) may be involved in brain tumours.

Gene alteration are frequent in many types of adenocarcinomas, below arelisted some genes that are mutated in many cancers:

Human breast cancer susceptibility (BRCA2) gene (seq id nos 35-94),Deleted in colorectal cancer (DCC) gene (seq id nos 30-34), Humanputatative mismatch repair/binding protein (hMSH3) gene (seq id nos134-147), Human hMSH6 gene (seq id nos 200-203 and 293-297), human N-MYCgene (seq id no 189-194), Human TGFb2 (hTGFb2) gene (seq id nos 22-29),Human p53 associated gene (seq id nos 285-292), Human MUC1 gene (seq idnos 247-266), Human germline n-myc gene (seq id nos 182-188), HumanWilm's tumour (WIT-1) associated protein (seq id nos 388-393), Humannasopharynx carcinoma EBV BNLF-1 gene (seq id nos 204-210), Humantransforming growth factor-beta induced gene product (BIGH3) seq id nos227-232).

Many of the mutated genes may result in development of leukemias andlymphomas: Human neurofibromin (NF1) gene (seq id nos 176-181), b-rafoncogene (seq id nos 170-175), Human protein-tyrosine kinase (JAK1) gene(seq id nos 267-271), Human protein-tyrosine kinase (JAK3) gene (seq idnos 272-279) are examples.

Genes involved in malignant melanoma: Human malignant melanoma(metastasis-supressor (hKiSS-1) gene (seq id nos 328-334), Genesinvolved in metastasis: Human metastasis-associated mta1 (hMTA1) gene(seq id nos 357-362).

Cell cycle control and signal transduction is strikcly regulated.Frameshift mutations in these genes may result in uncontrolled cellgrowth. Examples of genes which may be suseptable are: Human proteintyrosine phosphatase (hPTP) gene (seq id nos 95-102), Human kinase (TTK)gene (seq id nos 109-120), Human transcriptional repressor (CTCF) gene(seq id nos 121-127), Human cell cycle regulatory protein (E1A-bindingprotein) p300 gene (seq id nos 211-218), Human transforming growthfactor-beta induced gene product (BIGH3) (seq id nos 227-232), HumanFLt4 gene (for transmembrane tyrosinase kinase (seq id nos 280-284),Human G protein-coupled receptor (hGPR1) gene (seq id nos 314-319),Human transcription factor (hITF-2) gene (seq id nos 326-327), Humantelomerase-associated protein TP-1 (hTP-1) gene (seq id nos 335-348),Human transcription TFIIB 90 kDa subunit (hTFBIIB90) gene (seq id nos363-369), Human FADD-homologous ICE/CED-3like protease gene (seq id nos128-133)

Mutations in DNA synthesis or -repair enzymes may also lead touncontrolled cell growth. Human DNA topoisomerase II (top2) gene (seq idnos 103-108) and Human putative mismatch repair/binding protein (hMSH3)gene (seq id nos 134-1471 and (hMSH6) gene (seq id nos 200-203 and293-297).

The following are tumour suppressor genes, Human retinoblastoma bindingprotein 1 isoform I (hRBP1) gene (seq id nos 148-156), Humanneurofibromin (NF1) gene (seq id nos 176-181), Human p53 associated gene(seq id nos 285-292), Human retinoblastoma related protein (p107) gene(seq id nos 310-313), Human tumour suppressor (hLUCA-1) gene (seq id nos370-377), Mutations in these genes may result in development of cancer.

The following are oncogenes, proto-oncogenes or putative oncogenes;Human germline n-myc gene (seq id nos 182-188), Human n-myc gene (seq idnos 189-194), Human can (hCAN) gene (seq id nos 298-300), Human dek(hDEK) gene (seq id nos 307-309), b-raf oncogene (seq id nos 170-175),Human DBL (hDBL) proto-cogene/Human MCF2PO (hMCF2PO) gene (seq id nos301-306). Frameshift mutations in these genes may lead to development ofcancer.

BIOLOGICAL EXPERIMENTS DESCRIPTION OF THE FIGURES

FIG. 1:

It has been demonstrated that T cells from normal donors can bestimulated with a mixture of peptides containing both mutant BAX andmutant TGFβRII peptides. Peptide mixture dependent T cell proliferationin blood samples from six different donors are shown in FIG. 1. Theresults were obtained by stimulating peripheral blood mononuclear cells(PBMCs) from each donor with a mixture of mutant BAX peptides (seq idnos 1,9-12) and mutant TGFβRII peptides (seq id nos 15-21). Theconcentration of each individual peptide in the mixture was 20 μM. Aftertwo weeks, and weekly thereafter, the bulk cultures were restimulatedwith autologous PBMCs pulsed with 10-25 μM of the peptide mixture. After4-5 restimulations the bulk cultures were tested in a standardproliferation assay with PBMCs alone or as a control or PBMCs pulsedwith 25 μM of the peptides as antigen presenting cells (APCs)

FIG. 2:

It has further been found that T cell clones can be generated againstseparate peptides of the mixture used in the bulk stimulationexperiments. FIG. 2 shows the proliferation of T cell clone 521-2 whichwas obtained by cloning the bulk culture from donor 1 (FIG. 1) byseeding 5 cells per well in U-bottomed, 96-well microtiter plates andusing autologous PBMCs pulsed with 25 μM of the mutant BAX peptide withseq id no 12 as feeder cells. Autologous B-lymphoblastoid cells wereused as APCs in the proliferation assay.

FIG. 3:

In figure three it is shown that mutant BAX peptides and mutant TGFβRIIpeptides can be used to stimulate T cells (PBMCs) from a patient withbreast cancer. Dendritic cells (DCs) from the same cancer patient wereused as APCs. The T cell stimulation (FIG. 3) was obtained by pulsingDCs separately with a mixture of mutant BAX peptides (seq id nos 1,9-12)and a mixture of mutant TGFβRII peptides (seq id nos 15-21) followed byaddition of autologous PBMCs and 10 ng/ml tumour necrosis factor. Theconcentration of each peptide in the mixtures used for pulsing was 25μM. The PBMCs and the DCs were obtained by leukapheresis from a patientwith breast cancer who had been on a granulocyte colony stimulatingfactor (G-CSF) treatment. The CD34+ cells were isolated from the cellproduct before DCs were derived using standard methods.

FIG. 4:

FIG. 4 shows the capability of T cells obtained from ascites fluid of apancreatic cancer patient to recognise and proliferate to differentsynthetic peptides derived from mutant BAX (seq id nos 1,9-12) andmutant TGFβRII (seq id nos 15,17-21). The T cell line was obtained afterexpansion of T cells present in the ascites fluid of a patient withpancreatic adenocarcinoma. The T cell line was expanded in vitro byculturing with 100 U/ml recombinant interleukin-2 (rIL-2) (Amersham,Aylesbury, UK) for one week before being tested in a proliferationassay.

Autologous, irradiated (30 Gy) PBMCs were seeded 5×104 in u-bottomed96-well plates (Costar, Cambridge, Mass.) and pulsed with singlesynthetic peptides at 20 μM for 2 h. The T cells were added 5×104 perwell and the plates were incubated for four days at 37° C. with additionof 18.5×104 Bq/mL 3H-thymidine for the last 12 hours before harvesting.The plates were counted in a liquid scintillation counter (PackardTopcount). Data represent specific proliferation to the differentsynthetic peptides and values are expressed as the mean of triplicatecultures. These results show that T cells isolated from a pancreaticcancer patient are capable of responding to a panel of peptides carryingamino acid sequences derived from mutant BAX and TGFβRII.

FIG. 5:

FIG. 5 further demonstrates the capability T cells from anotherpancreatic cancer patient to recognise and proliferate to differentsynthetic peptides derived from mutant BAX and mutant TGFβRII. The Tcell line was obtained after expansion of T cells present in the ascitesfluid of a patient with pancreatic adencarcinoma. The experiment was setup in the same way as described above. Data represent specificproliferation to the different synthetic peptides and values areexpressed as the mean of triplicate cultures.

In order to investigate the T cell response from the latter pancreaticcancer patient, responding T cells were cloned. Peritoneal macrophageswere irradiated (30 Gy) and plated 1×104 into U-bottomed 96-well plates(Costar) together with 25 μM of each peptide. T cell blasts were countedin a microscope and added 5 blasts per well together with 100 U/ml humanrecombinant interleukin-2 (rIL-2) (Amersham, Aylesbury, UK) in a totalvolume of 200 mL. After 14 days T cell clones were transferred onto24-well plates (Costar) with 1 mg/mL phytohemagglutinin (PHA, Wellcome,Dartford, UK), 100 U/ml rIL-2 and allogeneic, irradiated PBMCs as feedercells and screened for peptide specificity after 7 and 14 days.

FIG. 6:

T cell clone 520.5, 520.7 and 520.8 were selected for furthercharacterisation and express the cell surface phenotype CD3+, CD8+ andTcR+. FIG. 6 shows the recognition and cytotoxicity of T cell clone520.5, 520.7 and 520.8 against peptide-pulsed autologous target cellspulsed with the seq id no 10 peptide. Autologous Epstein-barr virustransformed B-cells (EBV) were labelled with 3H-thymidine (9.25×104Bq/ml) over night, washed once and plated 2500 cells per well in 96-wellplates with or without 25 mM of synthetic peptide (seq id no 10) and 1%DMSO in medium. After 30 minutes incubation at 37° C. the plates werewashed before addition of T cells. The plates were further incubated at37° C. for 4 hours and then harvested before counting in a liquidscintillation counter (Packard Topcount). Data represent percentspecific lysis of 3H-thymidine labelled peptide pulsed target cells atan effector/target ratio of 10/1. Values are expressed as the mean oftriplicate cultures. These results demonstrate that the three differentT cell clones obtained from ascites fluid of a pancreatic carcinomapatient, exhibit specific cytotoxicity of autologous EBV targets pulsedwith the relevant peptide (seq id no 10) derived from mutant BAX.

FIG. 7:

FIG. 7 shows the cytolytic properties of three different T cell clonesobtained from the same patient. These T cell clones were cultured andexpanded as described above, but they were generated against a syntheticpeptide the seq id no 17 peptide carrying amino acid sequences derivedfrom mutant TGFβRII. T cell clone 538.1, 538.3 and 538.4 all show thecell-surface phenotype CD3+, CD8+ and TcR+. The experimental conditionswere as described above (FIG. 6). Data represent percent specific lysisof 3H-thymidine labelled peptide pulsed target cells pulsed with the seqid no 428 peptide at an effector/target ratio of 10/1. Values areexpressed as the mean of triplicate cultures. These results demonstratethat the three different T cell clones obtained from ascites fluid of apancreatic carcinoma patient, exhibit specific cytotoxicity ofautologous EBV targets pulsed with the relevant peptide (seq id no 428)derived from mutant TGFβRII.

FIG. 8:

FIG. 8 shows the specificity of two CD4+ T cell clones, IMT8 and IMT9,obtained from a tumour biopsy taken from a patient with anadenocarcinoma localised to the proximal colon. Immunohistochemistryrevealed that the patient had an abundant infiltrate of predominantlyCD4+ T cells, many of which carried activation markers. In areas of CD4T cell infiltration islands of HLA DR positive tumour cells wereobserved. The T cell clones were obtained from the component of tumourinfiltrating lymphocytes which grew out of the biopsy following culturein medium containing 15 U/ml of recombinant human IL-2 for 16 days. TheT cells from this culture were cloned by limiting dilution (1cells/well) in Terasaki plates with irradiated peptide pulsed APC and100 U/ml of IL-2. Pulsing of autologous APC was performed with a mixtureof the TGFβRII frameshift peptides with sequence identity no. 15, 17 and18 at 1 μg/ml of each peptide in the presence of 3 μg/ml of purifiedhuman β2 microglobulin and 10 ng/ml of recombinant human TNFα for 3 hrsat 37° C. Of the 14 clones that could be expanded preliminary testsshowed that two of the clones were reactive with the peptide mixtureused for cloning. After expansion the clones were screened forreactivity with the single peptides in a standard proliferative assay.The results show that IMT8 and IMT9 both react specifically with theTGFβRII frameshift peptide with seq. id. no. 17, no reactivity wasobserved with the two other frameshift peptides tested.

The figure (FIG. 8) depicts the results of conventional T cellproliferative assays, where cloned T cells (5×10⁴) and irradiated APC(5×10⁴) were cocultured for 3 days in triplicates before harvesting. Tomeasure the proliferative capacity of the cultures, ³H-thymidine (3,7×10⁴ Bq/well) was added to the culture overnight before harvesting)Values are given as mean counts per minute (cpm) of the triplicates.

FIG. 9:

FIG. 9 demonstrates that the specific reactivity of the two T cellclones IMT8 and IMT9 against the peptide with seq. id.no. 17 iscompletely blocked by treatment of the cells with an antibody thatspecifically binds to HLA-DR molecules, since the reactivity afterblocking is the same as the background reactivity of the clones with APCin the absence of the peptide. On the other hand antibodies to the HLAclass II isotypes HLA-DQ and -DP failed to block the reactivity of theclones with peptide pulsed APC. This experiment unequivocally identifiesHLA-DR as the molecule responsible to present the peptide to these two Tcell clones. Antibody blocking experiments were performed using thehomozygous EBV transformed cell line 9061 (IHWS9 nomenclature) as APC.The APC were pulsed with peptide at a concentration of 15 μg/ml for 1 hrat 37° C. before addition of blocking antibodies L243 (pan-DR antibody),SPVL3 (pan-DQ antibody) and B7.21 (pan-DP antibody) at 10 μg/ml.Unpulsed APC and APC pulsed with peptide in the absence of blockingantibody served as negative and positive controls respectively. Resultsare expressed as in FIG. 8.

FIG. 10:

The patient IMT was HLA typed and turned out to be HLA: A1,2; B7,8;DR3,14; DQ1,2. To determine which of the HLA-DR molecules that wereresponsible for presentation of the peptide with seq. id. no. 17, apanel of HLA workshop derived homozygous BCL cell lines were obtainedand pulsed with the peptide with seq. id. no. 17. FIG. 10 describes theidentification of HLA-DR14 (DRA*0102, DRB*1401) as the HLA-DR moleculeresponsible for presentation of the peptide with seq. id. no. 17 to theT cell clones IMT8 and IMT9. A specific proliferative response wasobserved when peptide was presented by the autologous EBV transformedcell line (Auto APC) and by cell lines 9054 (EK) and 9061 (31227ABO),both of which expressed DR14 as the only DR molecule on their surface.The homozygous cell line gave higher responses, reflecting a higherlevel of expression of the relevant class II/peptide complexes due tothe effect of a double dose of the genes encoding this DR molecule. Noresponse was obtained when the peptide was presented by cell linesexpressing HLA-DR3 (9018, LOO81785), which represents the other DRmolecule expressed by the patients APC, nor by irrelevant HLA-DRmolecules. The experiment was performed as described in FIG. 9, with theexception that no antibody blocking was performed. Results are expressedas in FIG. 8.

FIG. 11:

FIG. 11 describes the dose response curves obtained by pulsing the cellline 9054 with increasing concentrations of the peptide with seq. id.no. 17. Both IMT 8 and IMT9 demonstrate a dose dependent increase in theproliferative response to the peptide. Results were performed asdescribed in FIG. 9 and 10 with the peptide concentrations indicated onthe Figure (FIG. 11). Results are expressed as in FIG. 8.

FIG. 12:

FIG. 12 describes the reactivity of a cell line generated by in vitrostimulation of T cells isolated from peripheral blood from a healthyblood donor (Donor 2892) by weekly stimulation with irradiatedautologous dendritic cells pulsed with the peptides with sequenceidentity numbers 16, 17 and 21. A specific response above backgroundvalues was obtained when the T cells were co-incubated with autologousdendritic cells pulsed with the peptide with seq. id. no. 21. Noactivity could be detected in the culture after the first and second invitro stimulation. These data demonstrate that the T cell repertoire ofnormal individuals contain a few precursor cells that have the capacityto recognise this frameshift peptide derived from a mutation in TGFβRIIthat does not occur in normal people. In two other blood donors (#2706and #2896), the level of precursor cells with the relevant specificitywas too low to be detected. The results are expressed as spots per 10⁴ Tcells tested in a conventional IFNg ELISPOT assay. This assay enumeratesthe number of cells present in a mixture of cells that are capable ofspecifically reacting with a defined antigen. Briefly 10⁷ T cells (nonadherent cells) were stimulated weekly with 2-5×10⁶ irradiated peptidepulsed autologous dendritic cells (DC) as APC. The DC were generatedfrom the adherent cell population by culture for one week in recombinanthuman GM-CSF and IL-4 according to standard protocols as described inthe literature. After peptide pulsing overnight at 15 μg/ml of peptide,full maturation of the DC was obtained by culture with recombinant TNFα.ELISPOT was performed according to standard published protocols using10⁴ cultured T cells per well in duplicate and 10⁴ peptide pulsed orunpulsed DC as APC. The results are expressed as mean number of spotsper 10⁴ T cells.

FIG. 13:

FIG. 13 shows the results of in vitro stimulation of T cells from ahealthy blood donor (Donor 322) with peptides with sequence identitynumber 15-21. In vitro culture was performed as described in FIG. 12. Aproliferative response above background values was seen when the T cellculture primed with a mixture of the peptides with seq. id. no. 16 and21 was stimulated with peptide 21 and the culture primed with thepeptide with seq. id. no. 17 was stimulated with the same peptide. Theseresults demonstrate that normal blood donors have small numbers ofcirculating T cells specific for these frameshift peptides, and that itis possible to expand these cells in culture by stimulation withframeshift peptides. These results also confirmed the results shown inFIGS. 8-11, demonstrating that the peptide with seq. id. no. 17 isimmunogenic in humans, and indicate that the peptide with seq. id. no.21 may also be used as a cancer vaccine in humans. The results areexpressed as described in FIG. 8.

FIG. 14:

The results shown in FIG. 14 demonstrate that CD8+ T cells specific forHLA class I epitopes can be generated from T cells present in the T cellrepertoire of a healthy blood donor (donor 905). No reactivity abovebackground was seen with any of the peptides after the second round ofin vitro restimulation. After the fourth restimulation, the frequency ofT cells specific for the peptide with seq. id. no. 428 had increasedfrom undetectable levels to approximately 2,5% of the cells. Theseresults demonstrate that CTL precursors of the CD8+ phenotype arepresent in the unprimed T cell repertoire of healthy blood donors. SuchT cells may be expanded in vitro by specific stimulation with thepeptide with seq. id. no. 428. This forms the basis for using thispeptide as a cancer vaccine to elicit cytotoxic T cells specific forframeshift peptides in cancer patient having such mutations. T cellswere generated by weekly restimulation of T cells isolated fromperipheral blood and stimulated with peptide pulsed autologous DC asdescribed in FIG. 12, with the exception that Il-7 and Il-2 was addedduring culture according to standard procedures for generating cytotoxicT cells (CTL) of the CD8 phenotype. The peptides used were peptides withsequence identity number 428, 439, 446 and 451. Cells were tested inELISPOT assay as described in FIG. 12. The results are expressed asdescribed in FIG. 12.

The peptide with seq. id. no. 17 was selected and designed to containbinding motifs for both several HLA class I and HLA class II molecules.These peptides thus contains epitopes both for CD4+ and CD8+ T cells,and was predicted to elicit both CD4 and CD8 T cell responses in cancerpatient provided processing of the aberrant TGFβRII protein naturallyoccurring in cancer cells would take place and result in an overlappingpeptide. This has now been proven for CD4 T cells by the results inFIGS. 8-11. These results have the following implication:

1) The results in FIG. 8 prove that the mutated form of TGFβRII Receptorwhich occurs in a high proportion of cancer patients with defects intheir mismatch repair machinery is a tumour specific antigen.

2) The antigen specificity of the infiltrating T cells commonly observedin colorectal cancer are generally not known. The results in FIG. 8demonstrate that one component of the T cells constituting thepopulation of tumour infiltrating lymphocytes in this patients tumour isspecific for a frameshift mutation, demonstrating that TGFβRIIframeshift peptides are immunogenic in vivo, occasionally giving rise tospontaneous T cell activation.

3) It follows from this observation that processing of thenon-functional form of the TGFβRII Receptor that is formed by the commonframeshift mutation is processed. This processing may take place eitherin the tumour cell as part of natural breakdown of the aberrant protein,or after the tumour cell itself or a released form of the receptor hasbeen taken up by a professional APC or both.

4) The results in FIG. 8 also indicate that the peptide with seq. id.no. 17 is capable of binding to an HLA class II molecule, since pulsingof APC with this peptide results in a specific proliferative responseagainst the peptide, and since CD4 T cell responses always are class IIrestricted. That this is the case is demonstrated by the results of theexperiment shown in FIG. 9. Here it is shown that the specific responseagainst the peptide with seq. id. no. 17 is completely blocked by anantibody to HLA-DR, but not with antibodies to the two other HLA classII molecules, HLA-DQ and -DP. Furthermore, by using a panel of standardhomozygous Epstein Barr Virus (EBV) transformed B Cell Lines (BCL)covering the relevant HLA class II molecules present on the patients ownAPC, we were able to identify the class II molecule responsible forpresentation of the peptide with seq. id. no. 17 to TLC IMT8 and IMT9 asbeing HLA-DR 14. Together these findings fit extremely well with theimmunohistological observations made in parallel sections taken from thesame tumour biopsy, where we could show that activated CD4+ T cells wereabundant in the proximity of tumour cells that had been induced toexpress HLA-DR. molecules. The results in FIG. 11 demonstrate that theseT cell clones are capable of mounting a proliferative response over arange of peptide doses and that the responses are dose dependent.

5) Since these T cell clones were obtained by cloning T cells isolatedfrom a tumour biopsy, another implication of our finding is thatactivated T cells specific for the peptide with seq. id. no. 17 arecapable of homing to the tumour tissue after activation.

6) Since the peptide with seq. id. no. 17 is a tumour specific antigen,and since frameshift mutations giving rise to this peptide or peptideswith overlapping sequences are commonly found in cancers with defects inenzymes that are part of the mismatch repair machinery, this peptide maybe used as a vaccine to elicit T cell response in cancer patients orpatients at high risk for developing cancer. Such T cell responses maypotentially influence the growth of an existing tumour or prohibitregrowth of tumour after surgery and other forms of treatment or begiven to patients with an inheritable form of cancer where a defectmismatch enzyme is detected or suspected and that have a high chance ofdeveloping a cancer where this precise mismatch repair mutation willoccur.

SYNTHESIS

The peptides were synthesised by using continuous flow solid phasepeptide synthesis. N-a-Fmoc-amino acids with appropriate side chainprotection were used. The Fmoc-amino acids were activated for couplingas pentafluorophenyl esters or by using either TBTU or diisopropylcarbodiimide activation prior to coupling. 20% piperidine in DMF wasused for selective removal of Fmoc after each coupling. Cleavage fromthe resin and final removal of side chain protection was performed by95% TFA containing appropriate scavengers. The peptides were purifiedand analysed by reversed phase (C18) HPLC. The identity of the peptideswas confirmed by using electro-spray mass spectroscopy (Finnigan matSSQ710).

The peptides used for in vitro studies of T cell stimulation weresynthesised by this method.

Several other well known methods can be applied by a person skilled inthe art to synthesise the peptides.

Examples of the Method for Determining New Frameshift Mutation Peptides

In this Example, the BAX gene is used to illustrate the principle.

In each of the steps listed below, the 1st line is the gene sequence and2nd line is amino acid sequence.

In the steps 2-5, the outlined sequences represent the mutant part ofthe protein.

In the next Example, the TGFβRII gene is used to illustrate theprinciple.

In each of the steps listed below, the 1st line is the gene sequence and2nd line is amino acid sequence. In the steps 2-5, the outlinedsequences represent the mutant part of the protein.

Thus the peptides of the invention may be used in a method for thetreatment of cancers with cancer cells harbouring genes with frameshiftmutations, which treatment comprises administering at least one peptideof the present invention in vivo or ex vivo to a human patient in needof such treatment.

In another embodiment the peptides of the invention may be used tovaccinate a human being disposed for cancers with cancer cellsharbouring genes with frameshift mutations, by administering at leastone peptide of the present invention to said human being.

It is further considered to be an advantage to administer to a humanindividual a mixture of the peptides of this invention, whereby each ofthe peptides of the invention can bind to different types of HLA class Iand/or class II molecules of the individual.

It is further anticipated that the power of an anticancer vaccine orpeptide drug as disclosed in the above mentioned PCT/NO92/00032application, can be greatly enhanced if the peptides of the presentinvention were included. Thus in another embodiment of the presentinvention peptides of the present invention are administered togetherwith, either simultaneously or in optional sequence, with the peptidesdisclosed in PCT/NO92/00032.

It is considered that the peptides may be administered together, eithersimultaneously or separately, with compounds such as cytokines and/orgrowth factors, i.e. interleukin-2 (IL-2), interleukin-12 (IL-12),granulocyte macrophage colony stimulating factor (GM-CSF), Flt-3 ligandor the like in order to strengthen the immune response as known in theart.

The peptides according to the present invention can be used in a vaccineor a therapeutical composition either alone or in combination with othermaterials, such as for instance standard adjuvants or in the form of alipopeptide conjugate which as known in the art can induce high-affinitycytotoxic T lymphocytes, (K. Deres, Nature, Vol.342, (November 1989)).

The peptides according to the present invention may be useful to includein either a peptide or recombinant fragment based vaccine.

The peptides according to the present invention can be included inpharmaceutical compositions or in vaccines together with usualadditives, diluents, stabilisers or the like as known in the art.

According to this invention, a pharmaceutical composition or vaccine mayinclude the peptides alone or in combination with at least onepharmaceutically acceptable carrier or diluent.

Further a vaccine or therapeutical composition can comprise a selectionof peptides which are fragments of the mutant proteins arising frominsertion or deletion of bases in a repeat sequence of the gene.

Further a vaccine composition can comprise at least one peptide selectedfor one cancer, which vaccine would be administered to a person carryinga genetic disposition for this particular cancer.

Further a vaccine composition can comprise at least one peptide selectedfor one cancer, which vaccine would be administered to a personbelonging to a high risk group for this particular cancer.

The cancer vaccine according to this invention may further beadministered to the population in general for example as a mixture ofpeptides giving rise to T cell immunity against various common cancersconnected with frameshift mutation genes.

The peptides according to this invention may be administered as singlepeptides or as a mixture of peptides. Alternatively the peptides may becovalently linked with each other to form larger polypeptides or evencyclic polypeptides.

A cancer therapy according to the present invention may be administeredboth in vivo or ex vivo having as the main goal the raising of specificT cell lines or clones against the mutant gene product associated withthe cancer type with which the patient is afflicted.

Further, the frameshift mutant peptides of this invention may beadministered to a patient by various routes including but not limited tosubcutaneous, intramuscular, intradermal, intraperitoneal, intravenousor the like. In one embodiment the peptides of this invention areadministered intradermally. The peptides may be administered at singleor multiple injection sites to a patient in a therapeutically orprophylactically effective amount.

The peptides of this invention may be administered only once oralternatively several times, for instance once a week over a period of1-2 months with a repeated sequence later all according to the need ofthe patient being treated.

The peptides of this invention can be administered in an amount in therange of 1 microgram (1 μg) to 1 gram (1 g) to an average human patientor individual to be vaccinated. It is preferred to use a smaller dose inthe rage of 1 microgram (1 μg) to 1 milligram (1 mg) for eachadministration.

The invention further encompasses DNA sequences which encodes aframeshift mutation peptide.

The invention additionally encompasses isolated DNA sequences comprisinga DNA sequence encoding at least one frameshift mutant peptide, andadministration of such isolated DNA sequences as a vaccine for treatmentor prophylaxis of cancers associated with frameshift mutations in thegenes.

The peptides according to this invention may be administered to anindividual in the form of DNA vaccines. The DNA encoding these peptidesmay be in the form of cloned plasmid DNA or synthetic oligonucleotide.The DNA may be delivered together with cytokines, such as IL-2, and/orother co-stimulatory molecules. The cytokines and/or co-stimulatorymolecules may themselves be delivered in the form of plasmid oroligonucleotide DNA. The response to a DNA vaccine has been shown to beincreased by the presence of immunostimulatory DNA sequences (ISS).These can take the form of hexameric motifs containing methylated CpG,according to the formula:

5′-purine-purine-CG-pyrimidine-pyrimidine-3′. Our DNA vaccines maytherefore incorporate these or other ISS, in the DNA encoding thepeptides, in the DNA encoding the cytokine or other co-stimulatorymolecules, or in both. A review of the advantages of DNA vaccination isprovided by Tighe et al (1998, Immunology Today, 19(2), 89-97).

In one embodiment, the DNA sequence encoding the mutant BAX peptidescomprises:

Normal BAX.

ATG GGG GGG GAG GCA CCC GAG CTG GCC CTG GAC CCG GTG . . . .

1G deleted from BAX gene sequence.

ATG GGG GGG AGG CAC CCG AGC TGG CCC TGG ACC CGG TGC CTC AGG ATG CGT CCACCA AGA AGC TGA

2G deleted from BAX gene sequence.

ATG GGG GGA GGC ACC CGA GCT GGC CCT GGA CCC GGT GCC TCA GGA TGC GTC CACCAA GAA GCT GAG CGA GTG TCT CAA GCG CAT CGG GGA CGA ACT GGA CAG TAA

1G inserted in BAX gene sequence.

ATG GGG GGG GGA GGC ACC CGA GCT GGC CCT GGA CCC GGT GCC TCA GGA TGC GTCCAC CAA GAA GCT GAG CGA GTG TCT CAA GCG CAT CGG GAA CGA ACT GGA CAG TAA

2G inserted in BAX gene sequence.

ATG GGG GGG GGG AGG CAC CCG AGC TGG CCC TGG ACC CGG TGC CTC AGG ATG CGTCCA CCA AGA AGC TGA

In a second embodiment, the DNA sequence encoding the mutant TGFβRIIpeptides comprises:

Normal TGFβRII gene.

GAA AAA AAA AAG CCT GGT GAG ACT TTC TTC ATG TGT TCC . . . .

1A deleted from TGFβRII gene sequence.

GAA AAA AAA AGC CTG GTG AGA CTT TCT TCA TGT GTT CCT GTA GCT CTG ATG AGTGCA ATG ACA ACA TCA TCT TCT CAG AAG AAT ATA ACA CCA GCA ATC CTG ACT TGTTGC TAG

2A deleted from TGFβRII gene sequence.

GAA AAA AAA GCC TGG TGA

1A inserted in TGFβRII gene sequence.

GAA AAA AAA AAA GCC TGG TGA

2A inserted in TGFβRII gene sequence.

GAA AAA AAA AAA AGC CTG GTG AGA CTT TCT TCA TGT GTT CCT GTA GCT CTG ATGAGT GCA ATG ACA ACA TCA TCT TCT CAG AAG AAT ATA ACA CCA GCA ATC CTG ACTTGT TGC TAG

The invention further encompasses vectors and plasmids comprising a DNAsequence encoding a frameshift mutant peptide. The vectors include, butare not limited to E. Coli plasmid, a Listeria vector and recombinantviral vectors. Recombinant viral vectors include, but are not limited toorthopox virus, canary virus, capripox virus, suipox virus, vaccinia,baculovirus, human adenovirus, SV40, bovine papilloma virus and the likecomprising the DNA sequence encoding a frameshift mutant peptide.

It is considered that an anticancer treatment or prophylaxis may beachieved also through the administration of an effective amount of arecombinant virus vector or plasmid comprising at least one insertionsite containing a DNA sequence encoding a frameshift mutant peptide to apatient, whereby the patient's antigen presenting cells are turned intohost cells for the vector/plasmid and presentation of HLA/frameshiftmutation peptide complex is achieved.

A person skilled in the art will find other possible use combinationswith the peptides of this invention, and these are meant to beencompassed by the present claim.

The peptides according to this invention may be produced by conventionalprocesses as known in the art, such as chemical peptide synthesis,recombinant DNA technology or protease cleavage of a protein or peptideencoded by a frameshift mutated gene. One method for chemical synthesisis elucidated in the description below.

In order for a cancer vaccine and methods for specific cancer therapybased on specific T cell immunity to be effective, three conditions mustbe met:

1. The peptides used must correspond, either in their full length orafter processing by antigen presenting cells, to the processed mutantprotein fragment as presented by a HLA Class I and/or class II moleculeon the cancer cell or other antigen presenting cells,

2. The peptides used must be bound to a HLA Class I and/or Class IImolecule in an immunogenic form, and

3. T-cells capable of recognising and responding to the HLA/peptidecomplex must be present in the circulation of the human being.

It has been established that all these conditions are met for somerepresentative peptides according to the present invention. The peptidesaccording to the present invention give rise to specific T cell immuneresponses in vitro. It has been established that the peptides accordingto this invention correspond to processed mutant protein fragments. Thisis exemplified with peptides corresponding to fragments of transformedmutant BAX and TGFβRII peptides.

Through the present invention the following advantages are achieved:

It offers a possibility to treat patients suffering from cancers arisingfrom frame-shift mutations in their genes, most of which cancers knownat present do not have any good treatment alternatives.

It offers a possibility to vaccinate prophylaxtically humans carryinggenetic dispositions or belonging to other high risk groups.

It offers a possibility to prepare a combination treatment for aspecific cancer, such as for instance colorectal or pancreatic cancers,wherein the cancer commonly is associated with either a frameshiftmutation or a point mutation in the genes.

Since described frameshift mutations occurs in a large variety ofcancers it will be possible to use this peptides in combination withestablished vaccines and future vaccines to obtain a multiple targettingtreatment.

Likewise patients suffering from cancers associated with multipleframeshift mutations in genes can be treated more efficiently through acombination treatment.

459 1 18 PRT Homo sapiens 1 Arg His Pro Ser Trp Pro Trp Thr Arg Cys LeuArg Met Arg Pro Pro 1 5 10 15 Arg Ser 2 31 PRT Homo sapiens 2 Gly ThrArg Ala Gly Pro Gly Pro Gly Ala Ser Gly Cys Val His Gln 1 5 10 15 GluAla Glu Arg Val Ser Gln Ala His Arg Gly Arg Thr Gly Gln 20 25 30 3 32PRT Homo sapiens 3 Gly Gly Thr Arg Ala Gly Pro Gly Pro Gly Ala Ser GlyCys Val His 1 5 10 15 Gln Glu Ala Glu Arg Val Ser Gln Ala His Arg GlyArg Thr Gly Gln 20 25 30 4 19 PRT Homo sapiens 4 Gly Arg His Pro Ser TrpPro Trp Thr Arg Cys Leu Arg Met Arg Pro 1 5 10 15 Pro Arg Ser 5 28 PRTHomo sapiens 5 Ile Gln Asp Arg Ala Gly Arg Met Gly Gly Arg His Pro SerTrp Pro 1 5 10 15 Trp Thr Arg Cys Leu Arg Met Arg Pro Pro Arg Ser 20 256 19 PRT Homo sapiens 6 Ile Gln Asp Arg Ala Gly Arg Met Gly Gly Gly ArgHis Pro Ser Trp 1 5 10 15 Pro Trp Thr 7 42 PRT Homo sapiens 7 Ile GlnAsp Arg Ala Gly Arg Met Gly Gly Gly Gly Thr Arg Ala Gly 1 5 10 15 ProGly Pro Gly Ala Ser Gly Cys Val His Gln Glu Ala Glu Arg Val 20 25 30 SerGln Ala His Arg Gly Arg Thr Gly Gln 35 40 8 19 PRT Homo sapiens 8 IleGln Asp Arg Ala Gly Arg Met Gly Gly Gly Thr Arg Ala Gly Pro 1 5 10 15Gly Pro Gly 9 22 PRT Homo sapiens 9 Ile Gln Asp Arg Ala Gly Arg Met GlyGly Arg His Pro Ser Trp Pro 1 5 10 15 Trp Thr Arg Cys Leu Arg 20 10 22PRT Homo sapiens 10 Ala Ser Gly Cys Val His Gln Glu Ala Glu Arg Val SerGln Ala His 1 5 10 15 Arg Gly Arg Thr Gly Gln 20 11 22 PRT Homo sapiens11 Gly Gly Thr Arg Ala Gly Pro Gly Pro Gly Ala Ser Gly Cys Val His 1 510 15 Gln Glu Ala Glu Arg Val 20 12 22 PRT Homo sapiens 12 Ile Gln AspArg Ala Gly Arg Met Gly Gly Gly Gly Thr Arg Ala Gly 1 5 10 15 Pro GlyPro Gly Ala Ser 20 13 34 PRT Homo sapiens 13 Ser Leu Val Arg Leu Ser SerCys Val Pro Val Ala Leu Met Ser Ala 1 5 10 15 Met Thr Thr Ser Ser SerGln Lys Asn Ile Thr Pro Ala Ile Leu Thr 20 25 30 Cys Cys 14 44 PRT Homosapiens 14 Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Ser Leu Val Arg LeuSer 1 5 10 15 Ser Cys Val Pro Val Ala Leu Met Ser Ala Met Thr Thr SerSer Ser 20 25 30 Gln Lys Asn Ile Thr Pro Ala Ile Leu Thr Cys Cys 35 4015 19 PRT Homo sapiens 15 Pro Lys Cys Ile Met Lys Glu Lys Lys Lys SerLeu Val Arg Leu Ser 1 5 10 15 Ser Cys Val 16 23 PRT Homo sapiens 16 AlaLeu Met Ser Ala Met Thr Thr Ser Ser Ser Gln Lys Asn Ile Thr 1 5 10 15Pro Ala Ile Leu Thr Cys Cys 20 17 23 PRT Homo sapiens 17 Ser Leu Val ArgLeu Ser Ser Cys Val Pro Val Ala Leu Met Ser Ala 1 5 10 15 Met Thr ThrSer Ser Ser Gln 20 18 22 PRT Homo sapiens 18 Ser Pro Lys Cys Ile Met LysGlu Lys Lys Ser Leu Val Arg Leu Ser 1 5 10 15 Ser Cys Val Pro Val Ala 2019 12 PRT Homo sapiens 19 Ser Pro Lys Cys Ile Met Lys Glu Lys Lys AlaTrp 1 5 10 20 12 PRT Homo sapiens 20 Pro Lys Cys Ile Met Lys Glu Lys LysLys Ala Trp 1 5 10 21 19 PRT Homo sapiens 21 Ala Met Thr Thr Ser Ser SerGln Lys Asn Ile Thr Pro Ala Ile Leu 1 5 10 15 Thr Cys Cys 22 9 PRT Homosapiens 22 Thr Val Gly Arg Pro His Ile Ser Cys 1 5 23 10 PRT Homosapiens 23 Lys Thr Val Gly Arg Pro His Ile Ser Cys 1 5 10 24 18 PRT Homosapiens 24 Lys Gln Trp Glu Asp Pro Thr Ser Pro Ala Asn Val Ile Ala LeuLeu 1 5 10 15 Gln Thr 25 17 PRT Homo sapiens 25 Gln Trp Glu Asp Pro ThrSer Pro Ala Asn Val Ile Ala Leu Leu Gln 1 5 10 15 Thr 26 19 PRT Homosapiens 26 Gln Lys Thr Ile Lys Ser Thr Arg Lys Lys Thr Val Gly Arg ProHis 1 5 10 15 Ile Ser Cys 27 20 PRT Homo sapiens 27 Gln Lys Thr Ile LysSer Thr Arg Lys Lys Lys Thr Val Gly Arg Pro 1 5 10 15 His Ile Ser Cys 2028 28 PRT Homo sapiens 28 Gln Lys Thr Ile Lys Ser Thr Arg Lys Lys LysGln Trp Glu Asp Pro 1 5 10 15 Thr Ser Pro Ala Asn Val Ile Ala Leu LeuGln Thr 20 25 29 27 PRT Homo sapiens 29 Gln Lys Thr Ile Lys Ser Thr ArgLys Lys Gln Trp Glu Asp Pro Thr 1 5 10 15 Ser Pro Ala Asn Val Ile AlaLeu Leu Gln Thr 20 25 30 34 PRT Homo sapiens 30 Ala Ala Asp Leu Gln GlnGln Phe Val His Phe Leu Asp Cys Trp Asp 1 5 10 15 Val Ser Ser Ile ProPhe Thr Leu His Leu Pro Gln Ala Gln Asp Ile 20 25 30 Thr Thr 31 9 PRTHomo sapiens 31 Gly Lys Asp Ala Lys Glu Lys Ser Ser 1 5 32 10 PRT Homosapiens 32 Gly Lys Asp Ala Lys Glu Lys Lys Ser Ser 1 5 10 33 42 PRT Homosapiens 33 Gly Lys Asp Ala Lys Glu Lys Lys Ala Ala Asp Leu Gln Gln GlnPhe 1 5 10 15 Val His Phe Leu Asp Cys Trp Asp Val Ser Ser Ile Pro PheThr Leu 20 25 30 His Leu Pro Gln Ala Gln Asp Ile Thr Thr 35 40 34 41 PRTHomo sapiens 34 Gly Lys Asp Ala Lys Glu Lys Ala Ala Asp Leu Gln Gln GlnPhe Val 1 5 10 15 His Phe Leu Asp Cys Trp Asp Val Ser Ser Ile Pro PheThr Leu His 20 25 30 Leu Pro Gln Ala Gln Asp Ile Thr Thr 35 40 35 16 PRTHomo sapiens 35 Phe Ser Met Lys Gln Thr Leu Met Asn Val Lys Asn Leu LysThr Lys 1 5 10 15 36 17 PRT Homo sapiens 36 Lys Phe Ser Met Lys Gln ThrLeu Met Asn Val Lys Asn Leu Lys Thr 1 5 10 15 Lys 37 25 PRT Homo sapiens37 Val Arg Thr Ser Lys Thr Arg Lys Lys Phe Ser Met Lys Gln Thr Leu 1 510 15 Met Asn Val Lys Asn Leu Lys Thr Lys 20 25 38 26 PRT Homo sapiens38 Val Arg Thr Ser Lys Thr Arg Lys Lys Lys Phe Ser Met Lys Gln Thr 1 510 15 Leu Met Asn Val Lys Asn Leu Lys Thr Lys 20 25 39 12 PRT Homosapiens 39 Val Arg Thr Ser Lys Thr Arg Lys Lys Asn Phe Pro 1 5 10 40 11PRT Homo sapiens 40 Val Arg Thr Ser Lys Thr Arg Lys Asn Phe Pro 1 5 1041 10 PRT Homo sapiens 41 Ile Lys Lys Lys Leu Leu Gln Phe Gln Lys 1 5 1042 11 PRT Homo sapiens 42 Lys Ile Lys Lys Lys Leu Leu Gln Phe Gln Lys 15 10 43 17 PRT Homo sapiens 43 Lys Ser Arg Arg Asn Tyr Phe Asn Phe LysAsn Asn Cys Gln Ser Arg 1 5 10 15 Leu 44 16 PRT Homo sapiens 44 Ser ArgArg Asn Tyr Phe Asn Phe Lys Asn Asn Cys Gln Ser Arg Leu 1 5 10 15 45 18PRT Homo sapiens 45 Thr Asn Leu Arg Val Ile Gln Lys Ile Lys Lys Lys LeuLeu Gln Phe 1 5 10 15 Gln Lys 46 19 PRT Homo sapiens 46 Thr Asn Leu ArgVal Ile Gln Lys Lys Ile Lys Lys Lys Leu Leu Gln 1 5 10 15 Phe Gln Lys 4725 PRT Homo sapiens 47 Thr Asn Leu Arg Val Ile Gln Lys Lys Ser Arg ArgAsn Tyr Phe Asn 1 5 10 15 Phe Lys Asn Asn Cys Gln Ser Arg Leu 20 25 4824 PRT Homo sapiens 48 Thr Asn Leu Arg Val Ile Gln Lys Ser Arg Arg AsnTyr Phe Asn Phe 1 5 10 15 Lys Asn Asn Cys Gln Ser Arg Leu 20 49 5 PRTHomo sapiens 49 Lys Ile Met Ile Thr 1 5 50 12 PRT Homo sapiens 50 AsnIle Asp Lys Ile Pro Glu Lys Ile Met Ile Thr 1 5 10 51 13 PRT Homosapiens 51 Asn Ile Asp Lys Ile Pro Glu Lys Lys Ile Met Ile Thr 1 5 10 525 PRT Homo sapiens 52 Ile Ile Asn Ala Asn 1 5 53 6 PRT Homo sapiens 53Lys Ile Ile Asn Ala Asn 1 5 54 13 PRT Homo sapiens 54 Asn Asp Lys ThrVal Ser Glu Lys Ile Ile Asn Ala Asn 1 5 10 55 14 PRT Homo sapiens 55 AsnAsp Lys Thr Val Ser Glu Lys Lys Ile Ile Asn Ala Asn 1 5 10 56 14 PRTHomo sapiens 56 Asn Gly Leu Glu Lys Glu Tyr Leu Met Val Asn Gln Lys Glu1 5 10 57 23 PRT Homo sapiens 57 Ser Gln Thr Ser Leu Leu Glu Ala Lys AsnGly Leu Glu Lys Glu Tyr 1 5 10 15 Leu Met Val Asn Gln Lys Glu 20 58 24PRT Homo sapiens 58 Ser Gln Thr Ser Leu Leu Glu Ala Lys Lys Asn Gly LeuGlu Lys Glu 1 5 10 15 Tyr Leu Met Val Asn Gln Lys Glu 20 59 12 PRT Homosapiens 59 Ser Gln Thr Ser Leu Leu Glu Ala Lys Lys Met Ala 1 5 10 60 11PRT Homo sapiens 60 Ser Gln Thr Ser Leu Leu Glu Ala Lys Met Ala 1 5 1061 6 PRT Homo sapiens 61 Thr Leu Val Phe Pro Lys 1 5 62 7 PRT Homosapiens 62 Lys Thr Leu Val Phe Pro Lys 1 5 63 14 PRT Homo sapiens 63 LeuLys Asn Val Glu Asp Gln Lys Thr Leu Val Phe Pro Lys 1 5 10 64 15 PRTHomo sapiens 64 Leu Lys Asn Val Glu Asp Gln Lys Lys Thr Leu Val Phe ProLys 1 5 10 15 65 10 PRT Homo sapiens 65 Leu Lys Asn Val Glu Asp Gln LysLys His 1 5 10 66 9 PRT Homo sapiens 66 Leu Lys Asn Val Glu Asp Gln LysHis 1 5 67 6 PRT Homo sapiens 67 Lys Lys Ile Gln Leu Tyr 1 5 68 7 PRTHomo sapiens 68 Lys Lys Lys Ile Gln Leu Tyr 1 5 69 36 PRT Homo sapiens69 Arg Lys Arg Phe Ser Tyr Thr Glu Tyr Leu Ala Ser Ile Ile Arg Phe 1 510 15 Ile Phe Ser Val Asn Arg Arg Lys Glu Ile Gln Asn Leu Ser Ser Cys 2025 30 Asn Phe Lys Ile 35 70 15 PRT Homo sapiens 70 Leu Arg Ile Val SerTyr Ser Lys Lys Lys Lys Ile Gln Leu Tyr 1 5 10 15 71 16 PRT Homo sapiens71 Leu Arg Ile Val Ser Tyr Ser Lys Lys Lys Lys Lys Ile Gln Leu Tyr 1 510 15 72 45 PRT Homo sapiens 72 Leu Arg Ile Val Ser Tyr Ser Lys Lys ArgLys Arg Phe Ser Tyr Thr 1 5 10 15 Glu Tyr Leu Ala Ser Ile Ile Arg PheIle Phe Ser Val Asn Arg Arg 20 25 30 Lys Glu Ile Gln Asn Leu Ser Ser CysAsn Phe Lys Ile 35 40 45 73 44 PRT Homo sapiens 73 Leu Arg Ile Val SerTyr Ser Lys Arg Lys Arg Phe Ser Tyr Thr Glu 1 5 10 15 Tyr Leu Ala SerIle Ile Arg Phe Ile Phe Ser Val Asn Arg Arg Lys 20 25 30 Glu Ile Gln AsnLeu Ser Ser Cys Asn Phe Lys Ile 35 40 74 18 PRT Homo sapiens 74 Gln AspLeu Pro Leu Ser Ser Ile Cys Gln Thr Ile Val Thr Ile Tyr 1 5 10 15 TrpGln 75 19 PRT Homo sapiens 75 Lys Gln Asp Leu Pro Leu Ser Ser Ile CysGln Thr Ile Val Thr Ile 1 5 10 15 Tyr Trp Gln 76 25 PRT Homo sapiens 76Asn Arg Thr Cys Pro Phe Arg Leu Phe Val Arg Arg Met Leu Gln Phe 1 5 1015 Thr Gly Asn Lys Val Leu Asp Arg Pro 20 25 77 27 PRT Homo sapiens 77Gly Phe Val Val Ser Val Val Lys Lys Gln Asp Leu Pro Leu Ser Ser 1 5 1015 Ile Cys Gln Thr Ile Val Thr Ile Tyr Trp Gln 20 25 78 28 PRT Homosapiens 78 Gly Phe Val Val Ser Val Val Lys Lys Lys Gln Asp Leu Pro LeuSer 1 5 10 15 Ser Ile Cys Gln Thr Ile Val Thr Ile Tyr Trp Gln 20 25 7934 PRT Homo sapiens 79 Gly Phe Val Val Ser Val Val Lys Lys Asn Arg ThrCys Pro Phe Arg 1 5 10 15 Leu Phe Val Arg Arg Met Leu Gln Phe Thr GlyAsn Lys Val Leu Asp 20 25 30 Arg Pro 80 33 PRT Homo sapiens 80 Gly PheVal Val Ser Val Val Lys Asn Arg Thr Cys Pro Phe Arg Leu 1 5 10 15 PheVal Arg Arg Met Leu Gln Phe Thr Gly Asn Lys Val Leu Asp Arg 20 25 30 Pro81 8 PRT Homo sapiens 81 Tyr Arg Lys Thr Lys Asn Gln Asn 1 5 82 9 PRTHomo sapiens 82 Lys Tyr Arg Lys Thr Lys Asn Gln Asn 1 5 83 10 PRT Homosapiens 83 Asn Thr Glu Arg Pro Lys Ile Arg Thr Asn 1 5 10 84 17 PRT Homosapiens 84 Asp Glu Thr Phe Tyr Lys Gly Lys Lys Tyr Arg Lys Thr Lys AsnGln 1 5 10 15 Asn 85 18 PRT Homo sapiens 85 Asp Glu Thr Phe Tyr Lys GlyLys Lys Lys Tyr Arg Lys Thr Lys Asn 1 5 10 15 Gln Asn 86 19 PRT Homosapiens 86 Asp Glu Thr Phe Tyr Lys Gly Lys Lys Asn Thr Glu Arg Pro LysIle 1 5 10 15 Arg Thr Asn 87 18 PRT Homo sapiens 87 Asp Glu Thr Phe TyrLys Gly Lys Asn Thr Glu Arg Pro Lys Ile Arg 1 5 10 15 Thr Asn 88 28 PRTHomo sapiens 88 Leu Ser Ile Asn Asn Tyr Arg Phe Gln Met Lys Phe Tyr PheArg Phe 1 5 10 15 Thr Ser His Gly Ser Pro Phe Thr Ser Ala Asn Phe 20 2589 29 PRT Homo sapiens 89 Lys Leu Ser Ile Asn Asn Tyr Arg Phe Gln MetLys Phe Tyr Phe Arg 1 5 10 15 Phe Thr Ser His Gly Ser Pro Phe Thr SerAla Asn Phe 20 25 90 10 PRT Homo sapiens 90 Asn Ser Val Ser Thr Thr ThrGly Phe Arg 1 5 10 91 37 PRT Homo sapiens 91 Asn Ile Gln Leu Ala Ala ThrLys Lys Leu Ser Ile Asn Asn Tyr Arg 1 5 10 15 Phe Gln Met Lys Phe TyrPhe Arg Phe Thr Ser His Gly Ser Pro Phe 20 25 30 Thr Ser Ala Asn Phe 3592 38 PRT Homo sapiens 92 Asn Ile Gln Leu Ala Ala Thr Lys Lys Lys LeuSer Ile Asn Asn Tyr 1 5 10 15 Arg Phe Gln Met Lys Phe Tyr Phe Arg PheThr Ser His Gly Ser Pro 20 25 30 Phe Thr Ser Ala Asn Phe 35 93 19 PRTHomo sapiens 93 Asn Ile Gln Leu Ala Ala Thr Lys Lys Asn Ser Val Ser ThrThr Thr 1 5 10 15 Gly Phe Arg 94 18 PRT Homo sapiens 94 Asn Ile Gln LeuAla Ala Thr Lys Asn Ser Val Ser Thr Thr Thr Gly 1 5 10 15 Phe Arg 95 18PRT Homo sapiens 95 Met Glu His Val Ala Pro Gly Arg Met Ser Ala Ser ProGln Ser Pro 1 5 10 15 Thr Gln 96 19 PRT Homo sapiens 96 Lys Met Glu HisVal Ala Pro Gly Arg Met Ser Ala Ser Pro Gln Ser 1 5 10 15 Pro Thr Gln 9759 PRT Homo sapiens 97 Lys Trp Ser Thr Trp Leu Gln Ala Glu Cys Gln HisLeu His Ser Pro 1 5 10 15 Gln Arg Ser Asp Lys Pro Gln Gln Ala Gly LeuAsp Gln Gln His His 20 25 30 Cys Phe Ala Leu Asp Ser Ser Pro Gly Pro ArgPro Val Phe Leu Gln 35 40 45 Leu Leu Gly Leu Met Gly Gln Gly Arg His Asp50 55 98 58 PRT Homo sapiens 98 Trp Ser Thr Trp Leu Gln Ala Glu Cys GlnHis Leu His Ser Pro Gln 1 5 10 15 Arg Ser Asp Lys Pro Gln Gln Ala GlyLeu Asp Gln Gln His His Cys 20 25 30 Phe Ala Leu Asp Ser Ser Pro Gly ProArg Pro Val Phe Leu Gln Leu 35 40 45 Leu Gly Leu Met Gly Gln Gly Arg HisAsp 50 55 99 26 PRT Homo sapiens 99 Thr Phe Ser Val Trp Ala Glu Lys MetGlu His Val Ala Pro Gly Arg 1 5 10 15 Met Ser Ala Ser Pro Gln Ser ProThr Gln 20 25 100 27 PRT Homo sapiens 100 Thr Phe Ser Val Trp Ala GluLys Lys Met Glu His Val Ala Pro Gly 1 5 10 15 Arg Met Ser Ala Ser ProGln Ser Pro Thr Gln 20 25 101 67 PRT Homo sapiens 101 Thr Phe Ser ValTrp Ala Glu Lys Lys Trp Ser Thr Trp Leu Gln Ala 1 5 10 15 Glu Cys GlnHis Leu His Ser Pro Gln Arg Ser Asp Lys Pro Gln Gln 20 25 30 Ala Gly LeuAsp Gln Gln His His Cys Phe Ala Leu Asp Ser Ser Pro 35 40 45 Gly Pro ArgPro Val Phe Leu Gln Leu Leu Gly Leu Met Gly Gln Gly 50 55 60 Arg His Asp65 102 66 PRT Homo sapiens 102 Thr Phe Ser Val Trp Ala Glu Lys Trp SerThr Trp Leu Gln Ala Glu 1 5 10 15 Cys Gln His Leu His Ser Pro Gln ArgSer Asp Lys Pro Gln Gln Ala 20 25 30 Gly Leu Asp Gln Gln His His Cys PheAla Leu Asp Ser Ser Pro Gly 35 40 45 Pro Arg Pro Val Phe Leu Gln Leu LeuGly Leu Met Gly Gln Gly Arg 50 55 60 His Asp 65 103 18 PRT Homo sapiens103 His Lys Trp Leu Lys Phe Cys Leu Leu Arg Leu Val Lys Glu Ser Phe 1 510 15 His Glu 104 19 PRT Homo sapiens 104 Lys His Lys Trp Leu Lys PheCys Leu Leu Arg Leu Val Lys Glu Ser 1 5 10 15 Phe His Glu 105 27 PRTHomo sapiens 105 Lys Gly Gly Lys Ala Lys Gly Lys Lys His Lys Trp Leu LysPhe Cys 1 5 10 15 Leu Leu Arg Leu Val Lys Glu Ser Phe His Glu 20 25 10628 PRT Homo sapiens 106 Lys Gly Gly Lys Ala Lys Gly Lys Lys Lys His LysTrp Leu Lys Phe 1 5 10 15 Cys Leu Leu Arg Leu Val Lys Glu Ser Phe HisGlu 20 25 107 13 PRT Homo sapiens 107 Lys Gly Gly Lys Ala Lys Gly LysLys Asn Thr Asn Gly 1 5 10 108 12 PRT Homo sapiens 108 Lys Gly Gly LysAla Lys Gly Lys Asn Thr Asn Gly 1 5 10 109 8 PRT Homo sapiens 109 ValAsn Asn Phe Phe Lys Lys Leu 1 5 110 9 PRT Homo sapiens 110 Lys Val AsnAsn Phe Phe Lys Lys Leu 1 5 111 16 PRT Homo sapiens 111 Leu Ser Gln GlyAsn Val Lys Lys Val Asn Asn Phe Phe Lys Lys Leu 1 5 10 15 112 17 PRTHomo sapiens 112 Leu Ser Gln Gly Asn Val Lys Lys Lys Val Asn Asn Phe PheLys Lys 1 5 10 15 Leu 113 38 PRT Homo sapiens 113 Gly Glu Lys Asn AspLeu Gln Leu Phe Val Met Ser Asp Arg Arg Tyr 1 5 10 15 Lys Ile Tyr TrpThr Val Ile Leu Leu Asn Pro Cys Gly Asn Leu His 20 25 30 Leu Lys Thr ThrSer Leu 35 114 39 PRT Homo sapiens 114 Lys Gly Glu Lys Asn Asp Leu GlnLeu Phe Val Met Ser Asp Arg Arg 1 5 10 15 Tyr Lys Ile Tyr Trp Thr ValIle Leu Leu Asn Pro Cys Gly Asn Leu 20 25 30 His Leu Lys Thr Thr Ser Leu35 115 10 PRT Homo sapiens 115 Lys Gly Lys Lys Met Ile Cys Ser Tyr Ser 15 10 116 9 PRT Homo sapiens 116 Gly Lys Lys Met Ile Cys Ser Tyr Ser 1 5117 46 PRT Homo sapiens 117 Ser Ser Lys Thr Phe Glu Lys Lys Gly Glu LysAsn Asp Leu Gln Leu 1 5 10 15 Phe Val Met Ser Asp Arg Arg Tyr Lys IleTyr Trp Thr Val Ile Leu 20 25 30 Leu Asn Pro Cys Gly Asn Leu His Leu LysThr Thr Ser Leu 35 40 45 118 47 PRT Homo sapiens 118 Ser Ser Lys Thr PheGlu Lys Lys Lys Gly Glu Lys Asn Asp Leu Gln 1 5 10 15 Leu Phe Val MetSer Asp Arg Arg Tyr Lys Ile Tyr Trp Thr Val Ile 20 25 30 Leu Leu Asn ProCys Gly Asn Leu His Leu Lys Thr Thr Ser Leu 35 40 45 119 18 PRT Homosapiens 119 Ser Ser Lys Thr Phe Glu Lys Lys Lys Gly Lys Lys Met Ile CysSer 1 5 10 15 Tyr Ser 120 17 PRT Homo sapiens 120 Ser Ser Lys Thr PheGlu Lys Lys Gly Lys Lys Met Ile Cys Ser Tyr 1 5 10 15 Ser 121 17 PRTHomo sapiens 121 Gln Arg Lys Pro Lys Arg Ala Asn Cys Val Ile Gln Arg ArgAla Lys 1 5 10 15 Met 122 18 PRT Homo sapiens 122 Lys Gln Arg Lys ProLys Arg Ala Asn Cys Val Ile Gln Arg Arg Ala 1 5 10 15 Lys Met 123 26 PRTHomo sapiens 123 Asn Lys Glu Asn Gln Lys Glu Gln Thr Ala Leu Leu Tyr ArgGly Gly 1 5 10 15 Gln Arg Cys Arg Cys Val Cys Leu Arg Phe 20 25 124 26PRT Homo sapiens 124 Pro Asp Tyr Gln Pro Pro Ala Lys Lys Gln Arg Lys ProLys Arg Ala 1 5 10 15 Asn Cys Val Ile Gln Arg Arg Ala Lys Met 20 25 12527 PRT Homo sapiens 125 Pro Asp Tyr Gln Pro Pro Ala Lys Lys Lys Gln ArgLys Pro Lys Arg 1 5 10 15 Ala Asn Cys Val Ile Gln Arg Arg Ala Lys Met 2025 126 35 PRT Homo sapiens 126 Pro Asp Tyr Gln Pro Pro Ala Lys Lys AsnLys Glu Asn Gln Lys Glu 1 5 10 15 Gln Thr Ala Leu Leu Tyr Arg Gly GlyGln Arg Cys Arg Cys Val Cys 20 25 30 Leu Arg Phe 35 127 34 PRT Homosapiens 127 Pro Asp Tyr Gln Pro Pro Ala Lys Asn Lys Glu Asn Gln Lys GluGln 1 5 10 15 Thr Ala Leu Leu Tyr Arg Gly Gly Gln Arg Cys Arg Cys ValCys Leu 20 25 30 Arg Phe 128 7 PRT Homo sapiens 128 Asn Leu Ser Ser LeuLeu Ile 1 5 129 5 PRT Homo sapiens 129 Thr Cys Leu Pro Phe 1 5 130 15PRT Homo sapiens 130 Gln Pro Thr Phe Thr Leu Arg Lys Asn Leu Ser Ser LeuLeu Ile 1 5 10 15 131 16 PRT Homo sapiens 131 Gln Pro Thr Phe Thr LeuArg Lys Lys Asn Leu Ser Ser Leu Leu Ile 1 5 10 15 132 14 PRT Homosapiens 132 Gln Pro Thr Phe Thr Leu Arg Lys Lys Thr Cys Leu Pro Phe 1 510 133 13 PRT Homo sapiens 133 Gln Pro Thr Phe Thr Leu Arg Lys Thr CysLeu Pro Phe 1 5 10 134 31 PRT Homo sapiens 134 Arg Ala Thr Phe Leu LeuSer Leu Trp Glu Cys Ser Leu Pro Gln Ala 1 5 10 15 Arg Leu Cys Leu IleVal Ser Arg Thr Gly Leu Leu Val Gln Ser 20 25 30 135 19 PRT Homo sapiens135 Gly Gln His Phe Tyr Trp His Cys Gly Ser Ala Ala Cys His Arg Arg 1 510 15 Gly Cys Val 136 39 PRT Homo sapiens 136 Lys Glu Asn Val Arg AspLys Lys Arg Ala Thr Phe Leu Leu Ser Leu 1 5 10 15 Trp Glu Cys Ser LeuPro Gln Ala Arg Leu Cys Leu Ile Val Ser Arg 20 25 30 Thr Gly Leu Leu ValGln Ser 35 137 40 PRT Homo sapiens 137 Lys Glu Asn Val Arg Asp Lys LysLys Arg Ala Thr Phe Leu Leu Ser 1 5 10 15 Leu Trp Glu Cys Ser Leu ProGln Ala Arg Leu Cys Leu Ile Val Ser 20 25 30 Arg Thr Gly Leu Leu Val GlnSer 35 40 138 28 PRT Homo sapiens 138 Lys Glu Asn Val Arg Asp Lys LysLys Gly Gln His Phe Tyr Trp His 1 5 10 15 Cys Gly Ser Ala Ala Cys HisArg Arg Gly Cys Val 20 25 139 27 PRT Homo sapiens 139 Lys Glu Asn ValArg Asp Lys Lys Gly Gln His Phe Tyr Trp His Cys 1 5 10 15 Gly Ser AlaAla Cys His Arg Arg Gly Cys Val 20 25 140 39 PRT Homo sapiens 140 IleThr His Thr Arg Trp Gly Ile Thr Thr Trp Asp Ser Trp Ser Val 1 5 10 15Arg Met Lys Ala Asn Trp Ile Gln Ala Gln Gln Asn Lys Ser Leu Ile 20 25 30Leu Ser Pro Ser Phe Thr Lys 35 141 40 PRT Homo sapiens 141 Lys Ile ThrHis Thr Arg Trp Gly Ile Thr Thr Trp Asp Ser Trp Ser 1 5 10 15 Val ArgMet Lys Ala Asn Trp Ile Gln Ala Gln Gln Asn Lys Ser Leu 20 25 30 Ile LeuSer Pro Ser Phe Thr Lys 35 40 142 16 PRT Homo sapiens 142 Lys Leu LeuThr Pro Gly Gly Glu Leu Pro His Gly Ile Leu Gly Gln 1 5 10 15 143 15 PRTHomo sapiens 143 Leu Leu Thr Pro Gly Gly Glu Leu Pro His Gly Ile Leu GlyGln 1 5 10 15 144 47 PRT Homo sapiens 144 Pro Pro Val Cys Glu Leu GluLys Ile Thr His Thr Arg Trp Gly Ile 1 5 10 15 Thr Thr Trp Asp Ser TrpSer Val Arg Met Lys Ala Asn Trp Ile Gln 20 25 30 Ala Gln Gln Asn Lys SerLeu Ile Leu Ser Pro Ser Phe Thr Lys 35 40 45 145 48 PRT Homo sapiens 145Pro Pro Val Cys Glu Leu Glu Lys Lys Ile Thr His Thr Arg Trp Gly 1 5 1015 Ile Thr Thr Trp Asp Ser Trp Ser Val Arg Met Lys Ala Asn Trp Ile 20 2530 Gln Ala Gln Gln Asn Lys Ser Leu Ile Leu Ser Pro Ser Phe Thr Lys 35 4045 146 24 PRT Homo sapiens 146 Pro Pro Val Cys Glu Leu Glu Lys Lys LeuLeu Thr Pro Gly Gly Glu 1 5 10 15 Leu Pro His Gly Ile Leu Gly Gln 20 14723 PRT Homo sapiens 147 Pro Pro Val Cys Glu Leu Glu Lys Leu Leu Thr ProGly Gly Glu Leu 1 5 10 15 Pro His Gly Ile Leu Gly Gln 20 148 11 PRT Homosapiens 148 Ser Leu Lys Asp Glu Leu Glu Lys Met Lys Ile 1 5 10 149 12PRT Homo sapiens 149 Ser Leu Lys Asp Glu Leu Glu Lys Lys Met Lys Ile 1 510 150 12 PRT Homo sapiens 150 Leu Gly Gln Ser Ser Pro Glu Lys Lys AsnLys Asn 1 5 10 151 11 PRT Homo sapiens 151 Leu Gly Gln Ser Ser Pro GluLys Asn Lys Asn 1 5 10 152 23 PRT Homo sapiens 152 Arg Leu Arg Arg IleAsn Gly Arg Gly Ser Gln Ile Arg Ser Arg Asn 1 5 10 15 Ala Phe Asn ArgSer Glu Glu 20 153 10 PRT Homo sapiens 153 Glu Pro Lys Val Lys Glu GluLys Lys Thr 1 5 10 154 11 PRT Homo sapiens 154 Glu Pro Lys Val Lys GluGlu Lys Lys Lys Thr 1 5 10 155 32 PRT Homo sapiens 155 Glu Pro Lys ValLys Glu Glu Lys Lys Arg Leu Arg Arg Ile Asn Gly 1 5 10 15 Arg Gly SerGln Ile Arg Ser Arg Asn Ala Phe Asn Arg Ser Glu Glu 20 25 30 156 31 PRTHomo sapiens 156 Glu Pro Lys Val Lys Glu Glu Lys Arg Leu Arg Arg Ile AsnGly Arg 1 5 10 15 Gly Ser Gln Ile Arg Ser Arg Asn Ala Phe Asn Arg SerGlu Glu 20 25 30 157 14 PRT Homo sapiens 157 Thr Phe Arg Tyr Lys Gly LysGln His Pro Phe Phe Ser Thr 1 5 10 158 10 PRT Homo sapiens 158 Gly ProAsn Ala Pro Glu Glu Lys Asn His 1 5 10 159 11 PRT Homo sapiens 159 GlyPro Asn Ala Pro Glu Glu Lys Lys Asn His 1 5 10 160 23 PRT Homo sapiens160 Gly Pro Asn Ala Pro Glu Glu Lys Lys Thr Phe Arg Tyr Lys Gly Lys 1 510 15 Gln His Pro Phe Phe Ser Thr 20 161 22 PRT Homo sapiens 161 Gly ProAsn Ala Pro Glu Glu Lys Thr Phe Arg Tyr Lys Gly Lys Gln 1 5 10 15 HisPro Phe Phe Ser Thr 20 162 6 PRT Homo sapiens 162 Met Gln Asn Thr CysVal 1 5 163 7 PRT Homo sapiens 163 Lys Met Gln Asn Thr Cys Val 1 5 164 9PRT Homo sapiens 164 Lys Cys Lys Ile Arg Val Phe Ser Lys 1 5 165 8 PRTHomo sapiens 165 Cys Lys Ile Arg Val Phe Ser Lys 1 5 166 14 PRT Homosapiens 166 Phe Phe Lys Arg Thr Val Gln Lys Met Gln Asn Thr Cys Val 1 510 167 15 PRT Homo sapiens 167 Phe Phe Lys Arg Thr Val Gln Lys Lys MetGln Asn Thr Cys Val 1 5 10 15 168 17 PRT Homo sapiens 168 Phe Phe LysArg Thr Val Gln Lys Lys Cys Lys Ile Arg Val Phe Ser 1 5 10 15 Lys 169 16PRT Homo sapiens 169 Phe Phe Lys Arg Thr Val Gln Lys Cys Lys Ile Arg ValPhe Ser Lys 1 5 10 15 170 7 PRT Homo sapiens 170 Leu Pro His Tyr Leu AlaHis 1 5 171 8 PRT Homo sapiens 171 Cys Leu Ile Thr Trp Leu Thr Asn 1 5172 17 PRT Homo sapiens 172 Gly Ser Thr Thr Gly Leu Ser Ala Thr Pro LeuPro His Tyr Leu Ala 1 5 10 15 His 173 18 PRT Homo sapiens 173 Gly SerThr Thr Gly Leu Ser Ala Thr Pro Pro Leu Pro His Tyr Leu 1 5 10 15 AlaHis 174 19 PRT Homo sapiens 174 Gly Ser Thr Thr Gly Leu Ser Ala Thr ProPro Cys Leu Ile Thr Trp 1 5 10 15 Leu Thr Asn 175 18 PRT Homo sapiens175 Gly Ser Thr Thr Gly Leu Ser Ala Thr Pro Cys Leu Ile Thr Trp Leu 1 510 15 Thr Asn 176 9 PRT Homo sapiens 176 Arg Phe Ala Asp Lys Pro Arg ProAsn 1 5 177 20 PRT Homo sapiens 177 Asp Leu Pro Thr Ser Pro Asp Gln ThrArg Ser Gly Pro Val His Val 1 5 10 15 Ser Val Glu Pro 20 178 19 PRT Homosapiens 178 Asp Ser Ala Ala Gly Cys Ser Gly Thr Pro Arg Phe Ala Asp LysPro 1 5 10 15 Arg Pro Asn 179 20 PRT Homo sapiens 179 Asp Ser Ala AlaGly Cys Ser Gly Thr Pro Pro Arg Phe Ala Asp Lys 1 5 10 15 Pro Arg ProAsn 20 180 31 PRT Homo sapiens 180 Asp Ser Ala Ala Gly Cys Ser Gly ThrPro Pro Asp Leu Pro Thr Ser 1 5 10 15 Pro Asp Gln Thr Arg Ser Gly ProVal His Val Ser Val Glu Pro 20 25 30 181 30 PRT Homo sapiens 181 Asp SerAla Ala Gly Cys Ser Gly Thr Pro Asp Leu Pro Thr Ser Pro 1 5 10 15 AspGln Thr Arg Ser Gly Pro Val His Val Ser Val Glu Pro 20 25 30 182 53 PRTHomo sapiens 182 Ala His Pro Glu Thr Pro Ala Gln Asn Arg Leu Arg Ile ProCys Ser 1 5 10 15 Arg Arg Glu Val Arg Ser Arg Ala Cys Lys Pro Pro GlyAla Gln Gly 20 25 30 Ser Asp Glu Arg Arg Gly Lys Ala Ser Pro Gly Arg AspCys Asp Val 35 40 45 Arg Thr Gly Arg Pro 50 183 54 PRT Homo sapiens 183Pro Ala His Pro Glu Thr Pro Ala Gln Asn Arg Leu Arg Ile Pro Cys 1 5 1015 Ser Arg Arg Glu Val Arg Ser Arg Ala Cys Lys Pro Pro Gly Ala Gln 20 2530 Gly Ser Asp Glu Arg Arg Gly Lys Ala Ser Pro Gly Arg Asp Cys Asp 35 4045 Val Arg Thr Gly Arg Pro 50 184 20 PRT Homo sapiens 184 Arg Pro ThrArg Arg His Pro Arg Arg Ile Ala Ser Gly Ser Pro Ala 1 5 10 15 Val GlyGly Arg 20 185 63 PRT Homo sapiens 185 Val Ala Ile Arg Gly His Pro ArgPro Pro Ala His Pro Glu Thr Pro 1 5 10 15 Ala Gln Asn Arg Leu Arg IlePro Cys Ser Arg Arg Glu Val Arg Ser 20 25 30 Arg Ala Cys Lys Pro Pro GlyAla Gln Gly Ser Asp Glu Arg Arg Gly 35 40 45 Lys Ala Ser Pro Gly Arg AspCys Asp Val Arg Thr Gly Arg Pro 50 55 60 186 64 PRT Homo sapiens 186 ValAla Ile Arg Gly His Pro Arg Pro Pro Pro Ala His Pro Glu Thr 1 5 10 15Pro Ala Gln Asn Arg Leu Arg Ile Pro Cys Ser Arg Arg Glu Val Arg 20 25 30Ser Arg Ala Cys Lys Pro Pro Gly Ala Gln Gly Ser Asp Glu Arg Arg 35 40 45Gly Lys Ala Ser Pro Gly Arg Asp Cys Asp Val Arg Thr Gly Arg Pro 50 55 60187 30 PRT Homo sapiens 187 Val Ala Ile Arg Gly His Pro Arg Pro Pro ArgPro Thr Arg Arg His 1 5 10 15 Pro Arg Arg Ile Ala Ser Gly Ser Pro AlaVal Gly Gly Arg 20 25 30 188 29 PRT Homo sapiens 188 Val Ala Ile Arg GlyHis Pro Arg Pro Arg Pro Thr Arg Arg His Pro 1 5 10 15 Arg Arg Ile AlaSer Gly Ser Pro Ala Val Gly Gly Arg 20 25 189 85 PRT Homo sapiens 189Arg Gly Arg Thr Ser Gly Arg Ser Leu Ser Cys Cys Arg Arg Pro Arg 1 5 1015 Cys Arg Pro Ala Val Ala Ser Arg Ser Thr Ala Pro Ser Pro Arg Ala 20 2530 Gly Ser Arg Arg Cys Cys Leu Arg Thr Ser Cys Gly Ala Ala Arg Pro 35 4045 Arg Arg Thr Arg Ser Ala Cys Gly Asp Trp Val Ala Ser Pro Pro Thr 50 5560 Arg Ser Ser Ser Arg Thr Ala Cys Gly Ala Ala Ser Pro Pro Ala Arg 65 7075 80 Ser Trp Ser Ala Pro 85 190 8 PRT Homo sapiens 190 Gly Gly Gly HisLeu Glu Glu Val 1 5 191 94 PRT Homo sapiens 191 Tyr Phe Gly Gly Pro AspSer Thr Pro Arg Gly Arg Thr Ser Gly Arg 1 5 10 15 Ser Leu Ser Cys CysArg Arg Pro Arg Cys Arg Pro Ala Val Ala Ser 20 25 30 Arg Ser Thr Ala ProSer Pro Arg Ala Gly Ser Arg Arg Cys Cys Leu 35 40 45 Arg Thr Ser Cys GlyAla Ala Arg Pro Arg Arg Thr Arg Ser Ala Cys 50 55 60 Gly Asp Trp Val AlaSer Pro Pro Thr Arg Ser Ser Ser Arg Thr Ala 65 70 75 80 Cys Gly Ala AlaSer Pro Pro Ala Arg Ser Trp Ser Ala Pro 85 90 192 95 PRT Homo sapiens192 Tyr Phe Gly Gly Pro Asp Ser Thr Pro Pro Arg Gly Arg Thr Ser Gly 1 510 15 Arg Ser Leu Ser Cys Cys Arg Arg Pro Arg Cys Arg Pro Ala Val Ala 2025 30 Ser Arg Ser Thr Ala Pro Ser Pro Arg Ala Gly Ser Arg Arg Cys Cys 3540 45 Leu Arg Thr Ser Cys Gly Ala Ala Arg Pro Arg Arg Thr Arg Ser Ala 5055 60 Cys Gly Asp Trp Val Ala Ser Pro Pro Thr Arg Ser Ser Ser Arg Thr 6570 75 80 Ala Cys Gly Ala Ala Ser Pro Pro Ala Arg Ser Trp Ser Ala Pro 8590 95 193 18 PRT Homo sapiens 193 Tyr Phe Gly Gly Pro Asp Ser Thr ProPro Gly Gly Gly His Leu Glu 1 5 10 15 Glu Val 194 17 PRT Homo sapiens194 Tyr Phe Gly Gly Pro Asp Ser Thr Pro Gly Gly Gly His Leu Glu Glu 1 510 15 Val 195 6 PRT Homo sapiens 195 His Arg Val Ala Asp Pro 1 5 196 13PRT Homo sapiens 196 Leu Ser Gln Ser Ser Glu Leu Asp Pro Pro Ser Ser Arg1 5 10 197 14 PRT Homo sapiens 197 Leu Ser Gln Ser Ser Glu Leu Asp ProPro Pro Ser Ser Arg 1 5 10 198 16 PRT Homo sapiens 198 Leu Ser Gln SerSer Glu Leu Asp Pro Pro His Arg Val Ala Asp Pro 1 5 10 15 199 15 PRTHomo sapiens 199 Leu Ser Gln Ser Ser Glu Leu Asp Pro His Arg Val Ala AspPro 1 5 10 15 200 11 PRT Homo sapiens 200 Val Ile Leu Leu Pro Glu AspThr Pro Pro Ser 1 5 10 201 12 PRT Homo sapiens 201 Val Ile Leu Leu ProGlu Asp Thr Pro Pro Pro Ser 1 5 10 202 14 PRT Homo sapiens 202 Val IleLeu Leu Pro Glu Asp Thr Pro Pro Leu Leu Arg Ala 1 5 10 203 13 PRT Homosapiens 203 Val Ile Leu Leu Pro Glu Leu Asp Pro Leu Leu Arg Ala 1 5 10204 5 PRT Homo sapiens 204 Pro Ser Pro Leu Pro 1 5 205 25 PRT Homosapiens 205 Pro Leu Leu Phe His Arg Pro Cys Ser Pro Ser Pro Ala Leu GlyAla 1 5 10 15 Thr Val Leu Ala Val Tyr Arg Tyr Glu 20 25 206 24 PRT Homosapiens 206 Leu Leu Phe His Arg Pro Cys Ser Pro Ser Pro Ala Leu Gly AlaThr 1 5 10 15 Val Leu Ala Val Tyr Arg Tyr Glu 20 207 13 PRT Homo sapiens207 Ala Pro Arg Pro Pro Leu Gly Pro Pro Ser Pro Leu Pro 1 5 10 208 14PRT Homo sapiens 208 Ala Pro Arg Pro Pro Leu Gly Pro Pro Pro Ser Pro LeuPro 1 5 10 209 34 PRT Homo sapiens 209 Ala Pro Arg Pro Pro Leu Gly ProPro Pro Leu Leu Phe His Arg Pro 1 5 10 15 Cys Ser Pro Ser Pro Ala LeuGly Ala Thr Val Leu Ala Val Tyr Arg 20 25 30 Tyr Glu 210 33 PRT Homosapiens 210 Ala Pro Arg Pro Pro Leu Gly Pro Pro Leu Leu Phe His Arg ProCys 1 5 10 15 Ser Pro Ser Pro Ala Leu Gly Ala Thr Val Leu Ala Val TyrArg Tyr 20 25 30 Glu 211 28 PRT Homo sapiens 211 Thr Gln Val Leu Pro GlnGly Cys Ser Leu Ser Leu Leu His Thr Thr 1 5 10 15 Phe Pro His Arg GlnVal Pro His Ile Leu Asp Trp 20 25 212 29 PRT Homo sapiens 212 Pro ThrGln Val Leu Pro Gln Gly Cys Ser Leu Ser Leu Leu His Thr 1 5 10 15 ThrPhe Pro His Arg Gln Val Pro His Ile Leu Asp Trp 20 25 213 54 PRT Homosapiens 213 Pro Leu Gln Ser Phe Pro Lys Asp Ala Ala Ser Ala Phe Ser ThrPro 1 5 10 15 Arg Phe Pro Thr Asp Lys Phe Pro Thr Ser Trp Thr Gly SerCys Pro 20 25 30 Gly Gln Pro His Gly Thr Arg Ala Phe Cys Gln Pro Gly ProGlu Phe 35 40 45 Asn Ala Phe Ser Ala Cys 50 214 53 PRT Homo sapiens 214Leu Gln Ser Phe Pro Lys Asp Ala Ala Ser Ala Phe Ser Thr Pro Arg 1 5 1015 Phe Pro Thr Asp Lys Phe Pro Thr Ser Trp Thr Gly Ser Cys Pro Gly 20 2530 Gln Pro His Gly Thr Arg Ala Phe Cys Gln Pro Gly Pro Glu Phe Asn 35 4045 Ala Phe Ser Ala Cys 50 215 38 PRT Homo sapiens 215 Pro Ser Pro ArgPro Gln Ser Gln Pro Pro Thr Gln Val Leu Pro Gln 1 5 10 15 Gly Cys SerLeu Ser Leu Leu His Thr Thr Phe Pro His Arg Gln Val 20 25 30 Pro His IleLeu Asp Trp 35 216 39 PRT Homo sapiens 216 Pro Ser Pro Arg Pro Gln SerGln Pro Pro Pro Thr Gln Val Leu Pro 1 5 10 15 Gln Gly Cys Ser Leu SerLeu Leu His Thr Thr Phe Pro His Arg Gln 20 25 30 Val Pro His Ile Leu AspTrp 35 217 64 PRT Homo sapiens 217 Pro Ser Pro Arg Pro Gln Ser Gln ProPro Pro Leu Gln Ser Phe Pro 1 5 10 15 Lys Asp Ala Ala Ser Ala Phe SerThr Pro Arg Phe Pro Thr Asp Lys 20 25 30 Phe Pro Thr Ser Trp Thr Gly SerCys Pro Gly Gln Pro His Gly Thr 35 40 45 Arg Ala Phe Cys Gln Pro Gly ProGlu Phe Asn Ala Phe Ser Ala Cys 50 55 60 218 63 PRT Homo sapiens 218 ProSer Pro Arg Pro Gln Ser Gln Pro Pro Leu Gln Ser Phe Pro Lys 1 5 10 15Asp Ala Ala Ser Ala Phe Ser Thr Pro Arg Phe Pro Thr Asp Lys Phe 20 25 30Pro Thr Ser Trp Thr Gly Ser Cys Pro Gly Gln Pro His Gly Thr Arg 35 40 45Ala Phe Cys Gln Pro Gly Pro Glu Phe Asn Ala Phe Ser Ala Cys 50 55 60 21930 PRT Homo sapiens 219 Thr Ala Trp Pro Gly Arg Arg Arg Phe Thr Thr ProGlu Pro Tyr Cys 1 5 10 15 Leu Cys Thr Pro Leu Gly Pro Trp Ala Pro ArgPhe Leu Trp 20 25 30 220 31 PRT Homo sapiens 220 Pro Thr Ala Trp Pro GlyArg Arg Arg Phe Thr Thr Pro Glu Pro Tyr 1 5 10 15 Cys Leu Cys Thr ProLeu Gly Pro Trp Ala Pro Arg Phe Leu Trp 20 25 30 221 50 PRT Homo sapiens221 Pro Arg Pro Gly Pro Ala Gly Gly Ala Leu Leu Pro Arg Ser Leu Thr 1 510 15 Ala Phe Val Pro His Ser Gly His Gly Leu Pro Val Ser Ser Gly Glu 2025 30 Pro Ala Tyr Thr Pro Ile Pro His Asp Val Pro His Gly Thr Pro Pro 3540 45 Phe Cys 50 222 49 PRT Homo sapiens 222 Arg Pro Gly Pro Ala Gly GlyAla Leu Leu Pro Arg Ser Leu Thr Ala 1 5 10 15 Phe Val Pro His Ser GlyHis Gly Leu Pro Val Ser Ser Gly Glu Pro 20 25 30 Ala Tyr Thr Pro Ile ProHis Asp Val Pro His Gly Thr Pro Pro Phe 35 40 45 Cys 223 39 PRT Homosapiens 223 Asp Leu Pro Ala Val Pro Gly Pro Pro Thr Ala Trp Pro Gly ArgArg 1 5 10 15 Arg Phe Thr Thr Pro Glu Pro Tyr Cys Leu Cys Thr Pro LeuGly Pro 20 25 30 Trp Ala Pro Arg Phe Leu Trp 35 224 40 PRT Homo sapiens224 Asp Leu Pro Ala Val Pro Gly Pro Pro Pro Thr Ala Trp Pro Gly Arg 1 510 15 Arg Arg Phe Thr Thr Pro Glu Pro Tyr Cys Leu Cys Thr Pro Leu Gly 2025 30 Pro Trp Ala Pro Arg Phe Leu Trp 35 40 225 59 PRT Homo sapiens 225Asp Leu Pro Ala Val Pro Gly Pro Pro Pro Arg Pro Gly Pro Ala Gly 1 5 1015 Gly Ala Leu Leu Pro Arg Ser Leu Thr Ala Phe Val Pro His Ser Gly 20 2530 His Gly Leu Pro Val Ser Ser Gly Glu Pro Ala Tyr Thr Pro Ile Pro 35 4045 His Asp Val Pro His Gly Thr Pro Pro Phe Cys 50 55 226 58 PRT Homosapiens 226 Asp Leu Pro Ala Val Pro Gly Pro Pro Arg Pro Gly Pro Ala GlyGly 1 5 10 15 Ala Leu Leu Pro Arg Ser Leu Thr Ala Phe Val Pro His SerGly His 20 25 30 Gly Leu Pro Val Ser Ser Gly Glu Pro Ala Tyr Thr Pro IlePro His 35 40 45 Asp Val Pro His Gly Thr Pro Pro Phe Cys 50 55 227 8 PRTHomo sapiens 227 Gln Trp Gly Leu Ser Trp Met Ser 1 5 228 14 PRT Homosapiens 228 Asn Gly Asp Cys His Gly Cys Pro Glu Gly Arg Gln Ser Leu 1 510 229 17 PRT Homo sapiens 229 Phe Thr Met Asp Arg Val Leu Thr Pro GlnTrp Gly Leu Ser Trp Met 1 5 10 15 Ser 230 18 PRT Homo sapiens 230 PheThr Met Asp Arg Val Leu Thr Pro Pro Gln Trp Gly Leu Ser Trp 1 5 10 15Met Ser 231 24 PRT Homo sapiens 231 Phe Thr Met Asp Arg Val Leu Thr ProPro Asn Gly Asp Cys His Gly 1 5 10 15 Cys Pro Glu Gly Arg Gln Ser Leu 20232 23 PRT Homo sapiens 232 Phe Thr Met Asp Arg Val Leu Thr Pro Asn GlyAsp Cys His Gly Cys 1 5 10 15 Pro Glu Gly Arg Gln Ser Leu 20 233 115 PRTHomo sapiens 233 His His Pro Ala Arg Gln Cys Pro His Cys Ile Met His LeuGln Thr 1 5 10 15 Gln Leu Ile His Arg Asn Leu Thr Gly Pro Ser Gln LeuThr Ser Leu 20 25 30 His Arg Ser Pro Tyr Gln Ile Ala Ala Thr Pro Trp ThrThr Asp Phe 35 40 45 Ala Ala Ser Phe Phe Leu Asn Pro Val Thr Pro Phe LeuLeu Cys Arg 50 55 60 Arg Cys Gln Gly Lys Asp Val Leu Cys Thr Asn Ala ArgCys Leu Ser 65 70 75 80 Gln Thr Ser Pro Ser His His Lys Ala Leu Ser ArgThr Thr Thr Gln 85 90 95 Cys Met Asn Thr Thr Pro Trp Leu Ala Val Arg ProAla Lys Ala Phe 100 105 110 Pro Leu Leu 115 234 116 PRT Homo sapiens 234Pro His His Pro Ala Arg Gln Cys Pro His Cys Ile Met His Leu Gln 1 5 1015 Thr Gln Leu Ile His Arg Asn Leu Thr Gly Pro Ser Gln Leu Thr Ser 20 2530 Leu His Arg Ser Pro Tyr Gln Ile Ala Ala Thr Pro Trp Thr Thr Asp 35 4045 Phe Ala Ala Ser Phe Phe Leu Asn Pro Val Thr Pro Phe Leu Leu Cys 50 5560 Arg Arg Cys Gln Gly Lys Asp Val Leu Cys Thr Asn Ala Arg Cys Leu 65 7075 80 Ser Gln Thr Ser Pro Ser His His Lys Ala Leu Ser Arg Thr Thr Thr 8590 95 Gln Cys Met Asn Thr Thr Pro Trp Leu Ala Val Arg Pro Ala Lys Ala100 105 110 Phe Pro Leu Leu 115 235 23 PRT Homo sapiens 235 His Thr IleGln His Ala Ser Val Pro Thr Ala Ser Cys Ile Ser Lys 1 5 10 15 Leu AsnSer Tyr Thr Glu Asn 20 236 126 PRT Homo sapiens 236 Pro Gln Val Gly MetArg Pro Ser Asn Pro Pro His His Pro Ala Arg 1 5 10 15 Gln Cys Pro HisCys Ile Met His Leu Gln Thr Gln Leu Ile His Arg 20 25 30 Asn Leu Thr GlyPro Ser Gln Leu Thr Ser Leu His Arg Ser Pro Tyr 35 40 45 Gln Ile Ala AlaThr Pro Trp Thr Thr Asp Phe Ala Ala Ser Phe Phe 50 55 60 Leu Asn Pro ValThr Pro Phe Leu Leu Cys Arg Arg Cys Gln Gly Lys 65 70 75 80 Asp Val LeuCys Thr Asn Ala Arg Cys Leu Ser Gln Thr Ser Pro Ser 85 90 95 His His LysAla Leu Ser Arg Thr Thr Thr Gln Cys Met Asn Thr Thr 100 105 110 Pro TrpLeu Ala Val Arg Pro Ala Lys Ala Phe Pro Leu Leu 115 120 125 237 127 PRTHomo sapiens 237 Pro Gln Val Gly Met Arg Pro Ser Asn Pro Pro Pro His HisPro Ala 1 5 10 15 Arg Gln Cys Pro His Cys Ile Met His Leu Gln Thr GlnLeu Ile His 20 25 30 Arg Asn Leu Thr Gly Pro Ser Gln Leu Thr Ser Leu HisArg Ser Pro 35 40 45 Tyr Gln Ile Ala Ala Thr Pro Trp Thr Thr Asp Phe AlaAla Ser Phe 50 55 60 Phe Leu Asn Pro Val Thr Pro Phe Leu Leu Cys Arg ArgCys Gln Gly 65 70 75 80 Lys Asp Val Leu Cys Thr Asn Ala Arg Cys Leu SerGln Thr Ser Pro 85 90 95 Ser His His Lys Ala Leu Ser Arg Thr Thr Thr GlnCys Met Asn Thr 100 105 110 Thr Pro Trp Leu Ala Val Arg Pro Ala Lys AlaPhe Pro Leu Leu 115 120 125 238 34 PRT Homo sapiens 238 Pro Gln Val GlyMet Arg Pro Ser Asn Pro Pro His Thr Ile Gln His 1 5 10 15 Ala Ser ValPro Thr Ala Ser Cys Ile Ser Lys Leu Asn Ser Tyr Thr 20 25 30 Glu Asn 23933 PRT Homo sapiens 239 Pro Gln Val Gly Met Arg Pro Ser Asn Pro His ThrIle Gln His Ala 1 5 10 15 Ser Val Pro Thr Ala Ser Cys Ile Ser Lys LeuAsn Ser Tyr Thr Glu 20 25 30 Asn 240 51 PRT Homo sapiens 240 Trp Ala AlaArg Ser Trp Cys Glu Arg Arg Ala Ala Ala Val Ala Pro 1 5 10 15 Leu AlaPro Trp Ala Trp Gly Cys Pro Ala Gly Cys Thr Pro Pro Val 20 25 30 Ala AlaArg Ala Cys Ala Ala Thr Arg Pro Glu Gly Trp Arg Ser Pro 35 40 45 Cys ThrHis 50 241 52 PRT Homo sapiens 241 Pro Trp Ala Ala Arg Ser Trp Cys GluArg Arg Ala Ala Ala Val Ala 1 5 10 15 Pro Leu Ala Pro Trp Ala Trp GlyCys Pro Ala Gly Cys Thr Pro Pro 20 25 30 Val Ala Ala Arg Ala Cys Ala AlaThr Arg Pro Glu Gly Trp Arg Ser 35 40 45 Pro Cys Thr His 50 242 74 PRTHomo sapiens 242 Arg Gly Leu Arg Gly Ala Gly Ala Arg Gly Gly Leu Arg LeuLeu Arg 1 5 10 15 His Leu Arg Pro Gly Leu Gly Asp Ala Leu Arg Gly ValHis Pro Pro 20 25 30 Leu Arg Leu Gly Pro Ala Leu Leu Pro Ala Pro Arg GlyGly Glu Ala 35 40 45 Pro Ala His Thr Asp Ala Arg Ala Arg Arg Val His GlyAla Gly Gly 50 55 60 Asp Arg Gly His Pro Gly Pro Ala Ala Leu 65 70 24361 PRT Homo sapiens 243 Glu Glu Lys Leu Ala Arg Cys Arg Pro Pro Trp AlaAla Arg Ser Trp 1 5 10 15 Cys Glu Arg Arg Ala Ala Ala Val Ala Pro LeuAla Pro Trp Ala Trp 20 25 30 Gly Cys Pro Ala Gly Cys Thr Pro Pro Val AlaAla Arg Ala Cys Ala 35 40 45 Ala Thr Arg Pro Glu Gly Trp Arg Ser Pro CysThr His 50 55 60 244 62 PRT Homo sapiens 244 Glu Glu Lys Leu Ala Arg CysArg Pro Pro Pro Trp Ala Ala Arg Ser 1 5 10 15 Trp Cys Glu Arg Arg AlaAla Ala Val Ala Pro Leu Ala Pro Trp Ala 20 25 30 Trp Gly Cys Pro Ala GlyCys Thr Pro Pro Val Ala Ala Arg Ala Cys 35 40 45 Ala Ala Thr Arg Pro GluGly Trp Arg Ser Pro Cys Thr His 50 55 60 245 84 PRT Homo sapiens 245 GluGlu Lys Leu Ala Arg Cys Arg Pro Pro Arg Gly Leu Arg Gly Ala 1 5 10 15Gly Ala Arg Gly Gly Leu Arg Leu Leu Arg His Leu Arg Pro Gly Leu 20 25 30Gly Asp Ala Leu Arg Gly Val His Pro Pro Leu Arg Leu Gly Pro Ala 35 40 45Leu Leu Pro Ala Pro Arg Gly Gly Glu Ala Pro Ala His Thr Asp Ala 50 55 60Arg Ala Arg Arg Val His Gly Ala Gly Gly Asp Arg Gly His Pro Gly 65 70 7580 Pro Ala Ala Leu 246 83 PRT Homo sapiens 246 Glu Glu Lys Leu Ala ArgCys Arg Pro Arg Gly Leu Arg Gly Ala Gly 1 5 10 15 Ala Arg Gly Gly LeuArg Leu Leu Arg His Leu Arg Pro Gly Leu Gly 20 25 30 Asp Ala Leu Arg GlyVal His Pro Pro Leu Arg Leu Gly Pro Ala Leu 35 40 45 Leu Pro Ala Pro ArgGly Gly Glu Ala Pro Ala His Thr Asp Ala Arg 50 55 60 Ala Arg Arg Val HisGly Ala Gly Gly Asp Arg Gly His Pro Gly Pro 65 70 75 80 Ala Ala Leu 247163 PRT Homo sapiens 247 Gln Pro Pro Val Ser Pro Arg Pro Arg Arg Pro GlyArg Pro Arg Ala 1 5 10 15 Pro Pro Pro Pro Gln Pro Met Val Ser Pro ArgArg Arg Thr Thr Gly 20 25 30 Pro Pro Trp Arg Pro Pro Pro Leu Gln Ser ThrMet Ser Pro Pro Pro 35 40 45 Gln Ala Leu His Gln Ala Gln Leu Leu Leu TrpCys Thr Thr Ala Pro 50 55 60 Leu Pro Gly Leu Pro Gln Pro Gln Pro Ala ArgAla Leu His Ser Gln 65 70 75 80 Phe Pro Ala Thr Thr Leu Ile Leu Leu ProPro Leu Pro Ala Ile Ala 85 90 95 Pro Arg Leu Met Pro Val Ala Leu Thr IleAla Arg Tyr Leu Leu Ser 100 105 110 Pro Pro Pro Ile Thr Ala Leu Leu ProSer Cys Leu Leu Gly Ser Leu 115 120 125 Ser Phe Ser Cys Leu Phe Thr PheGln Thr Ser Ser Leu Ile Pro Leu 130 135 140 Trp Lys Ile Pro Ala Pro ThrThr Thr Lys Ser Cys Arg Glu Thr Phe 145 150 155 160 Leu Lys Trp 248 85PRT Homo sapiens 248 Ser Pro Gly Cys His Leu Gly Pro Gly Asp Gln Ala AlaPro Gly Leu 1 5 10 15 His Arg Pro Pro Ser Pro Trp Cys His Leu Gly AlaGly Gln Gln Ala 20 25 30 Arg Leu Gly Val His Arg Pro Ser Ser Pro Gln CysHis Leu Gly Leu 35 40 45 Arg Leu Cys Ile Arg Leu Ser Phe Tyr Ser Gly AlaGln Arg His Leu 50 55 60 Cys Gln Gly Tyr His Asn Pro Ser Gln Gln Glu HisSer Ile Leu Asn 65 70 75 80 Ser Gln Pro Pro Leu 85 249 172 PRT Homosapiens 249 Lys Pro Ala Pro Gly Ser Thr Ala Pro Gln Pro Pro Val Ser ProArg 1 5 10 15 Pro Arg Arg Pro Gly Arg Pro Arg Ala Pro Pro Pro Pro GlnPro Met 20 25 30 Val Ser Pro Arg Arg Arg Thr Thr Gly Pro Pro Trp Arg ProPro Pro 35 40 45 Leu Gln Ser Thr Met Ser Pro Pro Pro Gln Ala Leu His GlnAla Gln 50 55 60 Leu Leu Leu Trp Cys Thr Thr Ala Pro Leu Pro Gly Leu ProGln Pro 65 70 75 80 Gln Pro Ala Arg Ala Leu His Ser Gln Phe Pro Ala ThrThr Leu Ile 85 90 95 Leu Leu Pro Pro Leu Pro Ala Ile Ala Pro Arg Leu MetPro Val Ala 100 105 110 Leu Thr Ile Ala Arg Tyr Leu Leu Ser Pro Pro ProIle Thr Ala Leu 115 120 125 Leu Pro Ser Cys Leu Leu Gly Ser Leu Ser PheSer Cys Leu Phe Thr 130 135 140 Phe Gln Thr Ser Ser Leu Ile Pro Leu TrpLys Ile Pro Ala Pro Thr 145 150 155 160 Thr Thr Lys Ser Cys Arg Glu ThrPhe Leu Lys Trp 165 170 250 173 PRT Homo sapiens 250 Lys Pro Ala Pro GlySer Thr Ala Pro Pro Gln Pro Pro Val Ser Pro 1 5 10 15 Arg Pro Arg ArgPro Gly Arg Pro Arg Ala Pro Pro Pro Pro Gln Pro 20 25 30 Met Val Ser ProArg Arg Arg Thr Thr Gly Pro Pro Trp Arg Pro Pro 35 40 45 Pro Leu Gln SerThr Met Ser Pro Pro Pro Gln Ala Leu His Gln Ala 50 55 60 Gln Leu Leu LeuTrp Cys Thr Thr Ala Pro Leu Pro Gly Leu Pro Gln 65 70 75 80 Pro Gln ProAla Arg Ala Leu His Ser Gln Phe Pro Ala Thr Thr Leu 85 90 95 Ile Leu LeuPro Pro Leu Pro Ala Ile Ala Pro Arg Leu Met Pro Val 100 105 110 Ala LeuThr Ile Ala Arg Tyr Leu Leu Ser Pro Pro Pro Ile Thr Ala 115 120 125 LeuLeu Pro Ser Cys Leu Leu Gly Ser Leu Ser Phe Ser Cys Leu Phe 130 135 140Thr Phe Gln Thr Ser Ser Leu Ile Pro Leu Trp Lys Ile Pro Ala Pro 145 150155 160 Thr Thr Thr Lys Ser Cys Arg Glu Thr Phe Leu Lys Trp 165 170 25195 PRT Homo sapiens 251 Lys Pro Ala Pro Gly Ser Thr Ala Pro Pro Ser ProGly Cys His Leu 1 5 10 15 Gly Pro Gly Asp Gln Ala Ala Pro Gly Leu HisArg Pro Pro Ser Pro 20 25 30 Trp Cys His Leu Gly Ala Gly Gln Gln Ala ArgLeu Gly Val His Arg 35 40 45 Pro Ser Ser Pro Gln Cys His Leu Gly Leu ArgLeu Cys Ile Arg Leu 50 55 60 Ser Phe Tyr Ser Gly Ala Gln Arg His Leu CysGln Gly Tyr His Asn 65 70 75 80 Pro Ser Gln Gln Glu His Ser Ile Leu AsnSer Gln Pro Pro Leu 85 90 95 252 94 PRT Homo sapiens 252 Lys Pro Ala ProGly Ser Thr Ala Pro Ser Pro Gly Cys His Leu Gly 1 5 10 15 Pro Gly AspGln Ala Ala Pro Gly Leu His Arg Pro Pro Ser Pro Trp 20 25 30 Cys His LeuGly Ala Gly Gln Gln Ala Arg Leu Gly Val His Arg Pro 35 40 45 Ser Ser ProGln Cys His Leu Gly Leu Arg Leu Cys Ile Arg Leu Ser 50 55 60 Phe Tyr SerGly Ala Gln Arg His Leu Cys Gln Gly Tyr His Asn Pro 65 70 75 80 Ser GlnGln Glu His Ser Ile Leu Asn Ser Gln Pro Pro Leu 85 90 253 143 PRT Homosapiens 253 Gln Pro Met Val Ser Pro Arg Arg Arg Thr Thr Gly Pro Pro TrpArg 1 5 10 15 Pro Pro Pro Leu Gln Ser Thr Met Ser Pro Pro Pro Gln AlaLeu His 20 25 30 Gln Ala Gln Leu Leu Leu Trp Cys Thr Thr Ala Pro Leu ProGly Leu 35 40 45 Pro Gln Pro Gln Pro Ala Arg Ala Leu His Ser Gln Phe ProAla Thr 50 55 60 Thr Leu Ile Leu Leu Pro Pro Leu Pro Ala Ile Ala Pro ArgLeu Met 65 70 75 80 Pro Val Ala Leu Thr Ile Ala Arg Tyr Leu Leu Ser ProPro Pro Ile 85 90 95 Thr Ala Leu Leu Pro Ser Cys Leu Leu Gly Ser Leu SerPhe Ser Cys 100 105 110 Leu Phe Thr Phe Gln Thr Ser Ser Leu Ile Pro LeuTrp Lys Ile Pro 115 120 125 Ala Pro Thr Thr Thr Lys Ser Cys Arg Glu ThrPhe Leu Lys Trp 130 135 140 254 65 PRT Homo sapiens 254 Ser Pro Trp CysHis Leu Gly Ala Gly Gln Gln Ala Arg Leu Gly Val 1 5 10 15 His Arg ProSer Ser Pro Gln Cys His Leu Gly Leu Arg Leu Cys Ile 20 25 30 Arg Leu SerPhe Tyr Ser Gly Ala Gln Arg His Leu Cys Gln Gly Tyr 35 40 45 His Asn ProSer Gln Gln Glu His Ser Ile Leu Asn Ser Gln Pro Pro 50 55 60 Leu 65 25518 PRT Homo sapiens 255 Arg Pro Pro Pro Gly Ser Thr Ala Pro Gln Pro MetVal Ser Pro Arg 1 5 10 15 Arg Arg 256 19 PRT Homo sapiens 256 Arg ProPro Pro Gly Ser Thr Ala Pro Pro Gln Pro Met Val Ser Pro 1 5 10 15 ArgArg Arg 257 18 PRT Homo sapiens 257 Arg Pro Pro Pro Gly Ser Thr Ala ProPro Ser Pro Trp Cys His Leu 1 5 10 15 Gly Ala 258 17 PRT Homo sapiens258 Arg Pro Pro Pro Gly Ser Thr Ala Pro Ser Pro Trp Cys His Leu Gly 1 510 15 Ala 259 14 PRT Homo sapiens 259 Arg Pro Arg Ala Pro Pro Pro ProSer Pro Trp Cys His Leu 1 5 10 260 13 PRT Homo sapiens 260 Arg Pro ArgAla Pro Pro Pro Pro Pro Ser Pro Trp Cys 1 5 10 261 16 PRT Homo sapiens261 Arg Pro Arg Ala Pro Pro Pro Pro Ala His Gly Val Thr Ser Ala Pro 1 510 15 262 13 PRT Homo sapiens 262 Arg Pro Arg Ala Pro Pro Pro Pro ProAla His Gly Val 1 5 10 263 14 PRT Homo sapiens 263 Ala Pro Gly Leu HisArg Pro Pro Gln Pro Met Val Ser Pro 1 5 10 264 15 PRT Homo sapiens 264Ala Ala Pro Gly Leu His Arg Pro Gln Pro Met Val Ser Pro Arg 1 5 10 15265 13 PRT Homo sapiens 265 Pro Gly Leu His Arg Pro Pro Pro Ala His GlyVal Thr 1 5 10 266 14 PRT Homo sapiens 266 Ala Pro Gly Leu His Arg ProPro Ala His Gly Val Thr Ser 1 5 10 267 21 PRT Homo sapiens 267 Val AspArg Pro Gln His Thr Glu Trp Leu Ser Trp Ser Asn Leu Tyr 1 5 10 15 ArgIle Arg His Gln 20 268 10 PRT Homo sapiens 268 His Tyr Leu Cys Thr AspVal Ala Pro Arg 1 5 10 269 11 PRT Homo sapiens 269 His Tyr Leu Cys ThrAsp Val Ala Pro Pro Arg 1 5 10 270 31 PRT Homo sapiens 270 His Tyr LeuCys Thr Asp Val Ala Pro Pro Val Asp Arg Pro Gln His 1 5 10 15 Thr GluTrp Leu Ser Trp Ser Asn Leu Tyr Arg Ile Arg His Gln 20 25 30 271 30 PRTHomo sapiens 271 His Tyr Leu Cys Thr Asp Val Ala Pro Val Asp Arg Pro GlnHis Thr 1 5 10 15 Glu Trp Leu Ser Trp Ser Asn Leu Tyr Arg Ile Arg HisGln 20 25 30 272 108 PRT Homo sapiens 272 Ser Ala Tyr Leu Ser Pro LeuGly Thr Thr Trp Leu Arg Thr Cys Ala 1 5 10 15 Cys Arg Leu Pro Arg ProAla Ala Ser Cys Leu Cys Thr Thr Pro Ser 20 25 30 Leu Leu Trp Pro Arg ArgThr Cys Pro Ala Gly Ser Pro Arg Ala Thr 35 40 45 Ser Ser Pro Trp Arg MetPro Ala Pro Lys Ser Cys Cys Thr Thr Gly 50 55 60 Leu Ala Phe Thr Ser ProIle Gly Leu Gly Trp Arg Ser Ala Thr Ala 65 70 75 80 Ser Gly Tyr Ala ArgIle Trp Pro Val Leu Ser Leu Thr Cys Gln Ser 85 90 95 Trp Ser Thr Ser LeuPro Ser Thr Ala Val Thr Trp 100 105 273 109 PRT Homo sapiens 273 Pro SerAla Tyr Leu Ser Pro Leu Gly Thr Thr Trp Leu Arg Thr Cys 1 5 10 15 AlaCys Arg Leu Pro Arg Pro Ala Ala Ser Cys Leu Cys Thr Thr Pro 20 25 30 SerLeu Leu Trp Pro Arg Arg Thr Cys Pro Ala Gly Ser Pro Arg Ala 35 40 45 ThrSer Ser Pro Trp Arg Met Pro Ala Pro Lys Ser Cys Cys Thr Thr 50 55 60 GlyLeu Ala Phe Thr Ser Pro Ile Gly Leu Gly Trp Arg Ser Ala Thr 65 70 75 80Ala Ser Gly Tyr Ala Arg Ile Trp Pro Val Leu Ser Leu Thr Cys Gln 85 90 95Ser Trp Ser Thr Ser Leu Pro Ser Thr Ala Val Thr Trp 100 105 274 12 PRTHomo sapiens 274 Pro Ala Pro Ile Phe Leu Leu Trp Gly Pro Leu Gly 1 5 10275 11 PRT Homo sapiens 275 Ala Pro Ile Phe Leu Leu Trp Gly Pro Leu Gly1 5 10 276 117 PRT Homo sapiens 276 Leu Pro Ala Arg Ala Pro Gly Pro ProSer Ala Tyr Leu Ser Pro Leu 1 5 10 15 Gly Thr Thr Trp Leu Arg Thr CysAla Cys Arg Leu Pro Arg Pro Ala 20 25 30 Ala Ser Cys Leu Cys Thr Thr ProSer Leu Leu Trp Pro Arg Arg Thr 35 40 45 Cys Pro Ala Gly Ser Pro Arg AlaThr Ser Ser Pro Trp Arg Met Pro 50 55 60 Ala Pro Lys Ser Cys Cys Thr ThrGly Leu Ala Phe Thr Ser Pro Ile 65 70 75 80 Gly Leu Gly Trp Arg Ser AlaThr Ala Ser Gly Tyr Ala Arg Ile Trp 85 90 95 Pro Val Leu Ser Leu Thr CysGln Ser Trp Ser Thr Ser Leu Pro Ser 100 105 110 Thr Ala Val Thr Trp 115277 118 PRT Homo sapiens 277 Leu Pro Ala Arg Ala Pro Gly Pro Pro Pro SerAla Tyr Leu Ser Pro 1 5 10 15 Leu Gly Thr Thr Trp Leu Arg Thr Cys AlaCys Arg Leu Pro Arg Pro 20 25 30 Ala Ala Ser Cys Leu Cys Thr Thr Pro SerLeu Leu Trp Pro Arg Arg 35 40 45 Thr Cys Pro Ala Gly Ser Pro Arg Ala ThrSer Ser Pro Trp Arg Met 50 55 60 Pro Ala Pro Lys Ser Cys Cys Thr Thr GlyLeu Ala Phe Thr Ser Pro 65 70 75 80 Ile Gly Leu Gly Trp Arg Ser Ala ThrAla Ser Gly Tyr Ala Arg Ile 85 90 95 Trp Pro Val Leu Ser Leu Thr Cys GlnSer Trp Ser Thr Ser Leu Pro 100 105 110 Ser Thr Ala Val Thr Trp 115 27821 PRT Homo sapiens 278 Leu Pro Ala Arg Ala Pro Gly Pro Pro Pro Ala ProIle Phe Leu Leu 1 5 10 15 Trp Gly Pro Leu Gly 20 279 20 PRT Homo sapiens279 Leu Pro Ala Arg Ala Pro Gly Pro Pro Ala Pro Ile Phe Leu Leu Trp 1 510 15 Gly Pro Leu Gly 20 280 14 PRT Homo sapiens 280 Asp Leu Glu His HisGly Gly Val Thr Arg His Arg His Arg 1 5 10 281 11 PRT Homo sapiens 281Leu Val Ser Asp Tyr Ser Met Thr Pro Arg Pro 1 5 10 282 12 PRT Homosapiens 282 Leu Val Ser Asp Tyr Ser Met Thr Pro Pro Arg Pro 1 5 10 28324 PRT Homo sapiens 283 Leu Val Ser Asp Tyr Ser Met Thr Pro Pro Asp LeuGlu His His Gly 1 5 10 15 Gly Val Thr Arg His Arg His Arg 20 284 23 PRTHomo sapiens 284 Leu Val Ser Asp Tyr Ser Met Thr Pro Asp Leu Glu His HisGly Gly 1 5 10 15 Val Thr Arg His Arg His Arg 20 285 51 PRT Homo sapiens285 Phe His His Ile Ala Thr Asp Val Gly Pro Phe Val Arg Ile Gly Phe 1 510 15 Leu Lys Ile Lys Gly Lys Ile Lys Gly Lys Ser Leu Arg Lys Pro Asn 2025 30 Trp Lys Thr Gln His Lys Leu Lys Arg Ala Leu Met Phe Leu Ile Val 3540 45 Lys Lys Leu 50 286 52 PRT Homo sapiens 286 Pro Phe His His Ile AlaThr Asp Val Gly Pro Phe Val Arg Ile Gly 1 5 10 15 Phe Leu Lys Ile LysGly Lys Ile Lys Gly Lys Ser Leu Arg Lys Pro 20 25 30 Asn Trp Lys Thr GlnHis Lys Leu Lys Arg Ala Leu Met Phe Leu Ile 35 40 45 Val Lys Lys Leu 50287 12 PRT Homo sapiens 287 Pro Ser Ile Thr Leu Gln Gln Met Leu Ala ProSer 1 5 10 288 11 PRT Homo sapiens 288 Ser Ile Thr Leu Gln Gln Met LeuAla Pro Ser 1 5 10 289 60 PRT Homo sapiens 289 Thr Ser Cys Asn Glu MetAsn Pro Pro Phe His His Ile Ala Thr Asp 1 5 10 15 Val Gly Pro Phe ValArg Ile Gly Phe Leu Lys Ile Lys Gly Lys Ile 20 25 30 Lys Gly Lys Ser LeuArg Lys Pro Asn Trp Lys Thr Gln His Lys Leu 35 40 45 Lys Arg Ala Leu MetPhe Leu Ile Val Lys Lys Leu 50 55 60 290 61 PRT Homo sapiens 290 Thr SerCys Asn Glu Met Asn Pro Pro Pro Phe His His Ile Ala Thr 1 5 10 15 AspVal Gly Pro Phe Val Arg Ile Gly Phe Leu Lys Ile Lys Gly Lys 20 25 30 IleLys Gly Lys Ser Leu Arg Lys Pro Asn Trp Lys Thr Gln His Lys 35 40 45 LeuLys Arg Ala Leu Met Phe Leu Ile Val Lys Lys Leu 50 55 60 291 20 PRT Homosapiens 291 Thr Ser Cys Asn Glu Met Asn Pro Pro Ser Ile Thr Leu Gln GlnMet 1 5 10 15 Leu Ala Pro Ser 20 292 21 PRT Homo sapiens 292 Thr Ser CysAsn Glu Met Asn Pro Pro Pro Ser Ile Thr Leu Gln Gln 1 5 10 15 Met LeuAla Pro Ser 20 293 10 PRT Homo sapiens 293 Leu Glu Met Ile Leu Phe LeuMet Thr Phe 1 5 10 294 18 PRT Homo sapiens 294 His Pro Cys Ile Thr LysThr Phe Leu Glu Met Ile Leu Phe Leu Met 1 5 10 15 Thr Phe 295 19 PRTHomo sapiens 295 His Pro Cys Ile Thr Lys Thr Phe Phe Leu Glu Met Ile LeuPhe Leu 1 5 10 15 Met Thr Phe 296 11 PRT Homo sapiens 296 His Pro CysIle Thr Lys Thr Phe Phe Trp Arg 1 5 10 297 10 PRT Homo sapiens 297 HisPro Cys Ile Thr Lys Thr Phe Trp Arg 1 5 10 298 22 PRT Homo sapiens 298Leu Met Phe Glu His Ser Gln Met Arg Leu Asn Ser Lys Asn Ala His 1 5 1015 Leu Pro Ile Ile Ser Phe 20 299 30 PRT Homo sapiens 299 Glu Tyr GlySer Ile Ile Ala Phe Leu Met Phe Glu His Ser Gln Met 1 5 10 15 Arg LeuAsn Ser Lys Asn Ala His Leu Pro Ile Ile Ser Phe 20 25 30 300 31 PRT Homosapiens 300 Glu Tyr Gly Ser Ile Ile Ala Phe Phe Leu Met Phe Glu His SerGln 1 5 10 15 Met Arg Leu Asn Ser Lys Asn Ala His Leu Pro Ile Ile SerPhe 20 25 30 301 15 PRT Homo sapiens 301 His Leu Asn Lys Gly Arg Arg LeuGly Asp Lys Ile Arg Ala Thr 1 5 10 15 302 16 PRT Homo sapiens 302 PheHis Leu Asn Lys Gly Arg Arg Leu Gly Asp Lys Ile Arg Ala Thr 1 5 10 15303 23 PRT Homo sapiens 303 Val Thr Ser Gly Thr Pro Phe Phe His Leu AsnLys Gly Arg Arg Leu 1 5 10 15 Gly Asp Lys Ile Arg Ala Thr 20 304 24 PRTHomo sapiens 304 Val Thr Ser Gly Thr Pro Phe Phe Phe His Leu Asn Lys GlyArg Arg 1 5 10 15 Leu Gly Asp Lys Ile Arg Ala Thr 20 305 10 PRT Homosapiens 305 Val Thr Ser Gly Thr Pro Phe Phe Phe Ile 1 5 10 306 9 PRTHomo sapiens 306 Val Thr Ser Gly Thr Pro Phe Phe Ile 1 5 307 10 PRT Homosapiens 307 Cys Glu Ile Glu Arg Ile His Phe Phe Phe 1 5 10 308 11 PRTHomo sapiens 308 Cys Glu Ile Glu Arg Ile His Phe Phe Ser Lys 1 5 10 30910 PRT Homo sapiens 309 Cys Glu Ile Glu Arg Ile His Phe Ser Lys 1 5 10310 8 PRT Homo sapiens 310 Phe Arg Tyr Ile Ser Lys Ser Ile 1 5 311 7 PRTHomo sapiens 311 Arg Tyr Ile Ser Lys Ser Ile 1 5 312 16 PRT Homo sapiens312 Phe Lys Lys Tyr Glu Pro Ile Phe Phe Arg Tyr Ile Ser Lys Ser Ile 1 510 15 313 15 PRT Homo sapiens 313 Phe Lys Lys Tyr Glu Pro Ile Phe ArgTyr Ile Ser Lys Ser Ile 1 5 10 15 314 56 PRT Homo sapiens 314 Phe ProAsp Ser Asp Gln Pro Gly Pro Leu Tyr Pro Leu Asp Pro Ser 1 5 10 15 CysLeu Ile Ser Ser Ala Ser Asn Pro Gln Glu Leu Ser Asp Cys His 20 25 30 TyrIle His Leu Ala Phe Gly Phe Ser Asn Trp Arg Ser Cys Pro Val 35 40 45 LeuPro Gly His Cys Gly Val Gln 50 55 315 55 PRT Homo sapiens 315 Pro AspSer Asp Gln Pro Gly Pro Leu Tyr Pro Leu Asp Pro Ser Cys 1 5 10 15 LeuIle Ser Ser Ala Ser Asn Pro Gln Glu Leu Ser Asp Cys His Tyr 20 25 30 IleHis Leu Ala Phe Gly Phe Ser Asn Trp Arg Ser Cys Pro Val Leu 35 40 45 ProGly His Cys Gly Val Gln 50 55 316 9 PRT Homo sapiens 316 Leu Asn Met PheAla Ser Val Phe Ser 1 5 317 10 PRT Homo sapiens 317 Leu Asn Met Phe AlaSer Val Phe Phe Ser 1 5 10 318 64 PRT Homo sapiens 318 Leu Asn Met PheAla Ser Val Phe Phe Pro Asp Ser Asp Gln Pro Gly 1 5 10 15 Pro Leu TyrPro Leu Asp Pro Ser Cys Leu Ile Ser Ser Ala Ser Asn 20 25 30 Pro Gln GluLeu Ser Asp Cys His Tyr Ile His Leu Ala Phe Gly Phe 35 40 45 Ser Asn TrpArg Ser Cys Pro Val Leu Pro Gly His Cys Gly Val Gln 50 55 60 319 63 PRTHomo sapiens 319 Leu Asn Met Phe Ala Ser Val Phe Pro Asp Ser Asp Gln ProGly Pro 1 5 10 15 Leu Tyr Pro Leu Asp Pro Ser Cys Leu Ile Ser Ser AlaSer Asn Pro 20 25 30 Gln Glu Leu Ser Asp Cys His Tyr Ile His Leu Ala PheGly Phe Ser 35 40 45 Asn Trp Arg Ser Cys Pro Val Leu Pro Gly His Cys GlyVal Gln 50 55 60 320 63 PRT Homo sapiens 320 Ala Met Glu Glu Thr Val ValVal Ala Val Ala Thr Val Glu Thr Glu 1 5 10 15 Val Glu Ala Met Glu GluThr Gly Val Val Ala Ala Met Glu Glu Thr 20 25 30 Glu Val Gly Ala Thr GluGlu Thr Glu Val Ala Met Glu Ala Lys Trp 35 40 45 Glu Glu Glu Thr Thr ThrGlu Met Ile Ser Ala Thr Asp His Thr 50 55 60 321 55 PRT Homo sapiens 321Leu Trp Val Arg Pro Trp Leu Trp Glu Trp Leu Arg Trp Arg Pro Lys 1 5 1015 Trp Arg Leu Trp Arg Arg Gln Glu Trp Trp Arg Leu Trp Arg Arg Pro 20 2530 Arg Trp Gly Leu Arg Arg Arg Pro Arg Trp Leu Trp Arg Glu Asn Gly 35 4045 Arg Lys Lys Arg Leu Gln Lys 50 55 322 71 PRT Homo sapiens 322 Tyr GlyGly Asp Arg Ser Arg Gly Ala Met Glu Glu Thr Val Val Val 1 5 10 15 AlaVal Ala Thr Val Glu Thr Glu Val Glu Ala Met Glu Glu Thr Gly 20 25 30 ValVal Ala Ala Met Glu Glu Thr Glu Val Gly Ala Thr Glu Glu Thr 35 40 45 GluVal Ala Met Glu Ala Lys Trp Glu Glu Glu Thr Thr Thr Glu Met 50 55 60 IleSer Ala Thr Asp His Thr 65 70 323 72 PRT Homo sapiens 323 Tyr Gly GlyAsp Arg Ser Arg Gly Gly Ala Met Glu Glu Thr Val Val 1 5 10 15 Val AlaVal Ala Thr Val Glu Thr Glu Val Glu Ala Met Glu Glu Thr 20 25 30 Gly ValVal Ala Ala Met Glu Glu Thr Glu Val Gly Ala Thr Glu Glu 35 40 45 Thr GluVal Ala Met Glu Ala Lys Trp Glu Glu Glu Thr Thr Thr Glu 50 55 60 Met IleSer Ala Thr Asp His Thr 65 70 324 64 PRT Homo sapiens 324 Tyr Gly GlyAsp Arg Ser Arg Gly Gly Leu Trp Val Arg Pro Trp Leu 1 5 10 15 Trp GluTrp Leu Arg Trp Glu Pro Lys Trp Arg Leu Trp Arg Arg Gln 20 25 30 Glu TrpTrp Arg Leu Trp Arg Arg Pro Arg Trp Gly Leu Arg Arg Arg 35 40 45 Pro ArgTrp Leu Trp Arg Glu Asn Gly Arg Lys Lys Arg Leu Gln Lys 50 55 60 325 63PRT Homo sapiens 325 Tyr Gly Gly Asp Arg Ser Arg Gly Leu Trp Val Arg ProTrp Leu Trp 1 5 10 15 Glu Trp Leu Arg Trp Glu Pro Lys Trp Arg Leu TrpArg Arg Gln Glu 20 25 30 Trp Trp Arg Leu Trp Arg Arg Pro Arg Trp Gly LeuArg Arg Arg Pro 35 40 45 Arg Trp Leu Trp Arg Glu Asn Gly Arg Lys Lys ArgLeu Gln Lys 50 55 60 326 9 PRT Homo sapiens 326 Glu Phe Gly Gly Gly ArgArg Gln Lys 1 5 327 8 PRT Homo sapiens 327 Glu Phe Gly Gly Arg Arg GlnLys 1 5 328 15 PRT Homo sapiens 328 Arg Arg Ala Lys Gly Gly Gly Ala GlyAla Ser Asn Pro Arg Gln 1 5 10 15 329 16 PRT Homo sapiens 329 Gly ArgArg Ala Lys Gly Gly Gly Ala Gly Ala Ser Asn Pro Arg Gln 1 5 10 15 330 21PRT Homo sapiens 330 Asp Val Gly Leu Arg Glu Gly Ala Leu Glu Leu Pro ThrArg Gly Asn 1 5 10 15 Lys Arg Asn Val Ala 20 331 24 PRT Homo sapiens 331Met Arg Gly Gly Gly Gly Val Gly Gly Arg Arg Ala Lys Gly Gly Gly 1 5 1015 Ala Gly Ala Ser Asn Pro Arg Gln 20 332 25 PRT Homo sapiens 332 MetArg Gly Gly Gly Gly Val Gly Gly Gly Arg Arg Ala Lys Gly Gly 1 5 10 15Gly Ala Gly Ala Ser Asn Pro Arg Gln 20 25 333 30 PRT Homo sapiens 333Met Arg Gly Gly Gly Gly Val Gly Gly Asp Val Gly Leu Arg Glu Gly 1 5 1015 Ala Leu Glu Leu Pro Thr Arg Gly Asn Lys Arg Asn Val Ala 20 25 30 33429 PRT Homo sapiens 334 Met Arg Gly Gly Gly Gly Val Gly Asp Val Gly LeuArg Glu Gly Ala 1 5 10 15 Leu Glu Leu Pro Thr Arg Gly Asn Lys Arg AsnVal Ala 20 25 335 25 PRT Homo sapiens 335 Val Trp Gln Leu Ala Gly ProMet Leu Ala Gly Trp Arg Ser Leu Gly 1 5 10 15 Ser Trp Phe Cys Arg MetTyr Gly Ile 20 25 336 46 PRT Homo sapiens 336 Cys Gly Ser Trp Pro AlaLeu Cys Trp Arg Ala Gly Gly Val Trp Ala 1 5 10 15 Val Gly Ser Ala GlyCys Met Glu Tyr Asp Pro Glu Ala Leu Pro Ala 20 25 30 Ala Trp Gly Pro AlaAla Ala Ala Thr Val His Pro Arg Arg 35 40 45 337 33 PRT Homo sapiens 337Arg Arg Tyr Pro Cys Glu Trp Gly Val Trp Gln Leu Ala Gly Pro Met 1 5 1015 Leu Ala Gly Trp Arg Ser Leu Gly Ser Trp Phe Cys Arg Met Tyr Gly 20 2530 Ile 338 34 PRT Homo sapiens 338 Arg Arg Tyr Pro Cys Glu Trp Gly GlyVal Trp Gln Leu Ala Gly Pro 1 5 10 15 Met Leu Ala Gly Trp Arg Ser LeuGly Ser Trp Phe Cys Arg Met Tyr 20 25 30 Gly Ile 339 55 PRT Homo sapiens339 Arg Arg Tyr Pro Cys Glu Trp Gly Gly Cys Gly Ser Trp Pro Ala Leu 1 510 15 Cys Trp Arg Ala Gly Gly Val Trp Ala Val Gly Ser Ala Gly Cys Met 2025 30 Glu Tyr Asp Pro Glu Ala Leu Pro Ala Ala Trp Gly Pro Ala Ala Ala 3540 45 Ala Thr Val His Pro Arg Arg 50 55 340 54 PRT Homo sapiens 340 ArgArg Tyr Pro Cys Glu Trp Gly Cys Gly Ser Trp Pro Ala Leu Cys 1 5 10 15Trp Arg Ala Gly Gly Val Trp Ala Val Gly Ser Ala Gly Cys Met Glu 20 25 30Tyr Asp Pro Glu Ala Leu Pro Ala Ala Trp Gly Pro Ala Ala Ala Ala 35 40 45Thr Val His Pro Arg Arg 50 341 43 PRT Homo sapiens 341 Leu Trp Leu TrpAla Gly Trp Thr Val Trp Trp Ser Cys Gly Pro Gly 1 5 10 15 Glu Lys GlyHis Gly Trp Pro Ser Leu Pro Thr Met Ala Leu Leu Leu 20 25 30 Leu Arg PheSer Cys Met Arg Val Ala Ser Tyr 35 40 342 44 PRT Homo sapiens 342 GlyLeu Trp Leu Trp Ala Gly Trp Thr Val Trp Trp Ser Cys Gly Pro 1 5 10 15Gly Glu Lys Gly His Gly Trp Pro Ser Leu Pro Thr Met Ala Leu Leu 20 25 30Leu Leu Arg Phe Ser Cys Met Arg Val Ala Ser Tyr 35 40 343 84 PRT Homosapiens 343 Gly Cys Gly Cys Gly Pro Ala Gly Gln Tyr Gly Gly Ala Val GlyLeu 1 5 10 15 Ala Arg Arg Gly Thr Ala Gly Cys Leu Pro Cys Pro Pro TrpLeu Cys 20 25 30 Cys Cys Cys Ala Phe Pro Ala Cys Gly Leu Pro Gly Thr AspGly Trp 35 40 45 Arg Gly Trp Gln Gly Ser Gly Cys Val Arg Val Ser Gly SerAla Pro 50 55 60 Trp Ala Pro Gly Phe Pro Phe Ser Pro Pro Cys Pro Leu CysGly Thr 65 70 75 80 Gln Pro Arg Trp 344 83 PRT Homo sapiens 344 Cys GlyCys Gly Pro Ala Gly Gln Tyr Gly Gly Ala Val Gly Leu Ala 1 5 10 15 ArgArg Gly Thr Ala Gly Cys Leu Pro Cys Pro Pro Trp Leu Cys Cys 20 25 30 CysCys Ala Phe Pro Ala Cys Gly Leu Pro Gly Thr Asp Gly Trp Arg 35 40 45 GlyTrp Gln Gly Ser Gly Cys Val Arg Val Ser Gly Ser Ala Pro Trp 50 55 60 AlaPro Gly Phe Pro Phe Ser Pro Pro Cys Pro Leu Cys Gly Thr Gln 65 70 75 80Pro Arg Trp 345 51 PRT Homo sapiens 345 Leu Ala Phe Asn Val Pro Gly GlyLeu Trp Leu Trp Ala Gly Trp Thr 1 5 10 15 Val Trp Trp Ser Cys Gly ProGly Glu Lys Gly His Gly Trp Pro Ser 20 25 30 Leu Pro Thr Met Ala Leu LeuLeu Leu Arg Phe Ser Cys Met Arg Val 35 40 45 Ala Ser Tyr 50 346 52 PRTHomo sapiens 346 Leu Ala Phe Asn Val Pro Gly Gly Gly Leu Trp Leu Trp AlaGly Trp 1 5 10 15 Thr Val Trp Trp Ser Cys Gly Pro Gly Glu Lys Gly HisGly Trp Pro 20 25 30 Ser Leu Pro Thr Met Ala Leu Leu Leu Leu Arg Phe SerCys Met Arg 35 40 45 Val Ala Ser Tyr 50 347 92 PRT Homo sapiens 347 LeuAla Phe Asn Val Pro Gly Gly Gly Cys Gly Cys Gly Pro Ala Gly 1 5 10 15Gln Tyr Gly Gly Ala Val Gly Leu Ala Arg Arg Gly Thr Ala Gly Cys 20 25 30Leu Pro Cys Pro Pro Trp Leu Cys Cys Cys Cys Ala Phe Pro Ala Cys 35 40 45Gly Leu Pro Gly Thr Asp Gly Trp Arg Gly Trp Gln Gly Ser Gly Cys 50 55 60Val Arg Val Ser Gly Ser Ala Pro Trp Ala Pro Gly Phe Pro Phe Ser 65 70 7580 Pro Pro Cys Pro Leu Cys Gly Thr Gln Pro Arg Trp 85 90 348 91 PRT Homosapiens 348 Leu Ala Phe Asn Val Pro Gly Gly Cys Gly Cys Gly Pro Ala GlyGln 1 5 10 15 Tyr Gly Gly Ala Val Gly Leu Ala Arg Arg Gly Thr Ala GlyCys Leu 20 25 30 Pro Cys Pro Pro Trp Leu Cys Cys Cys Cys Ala Phe Pro AlaCys Gly 35 40 45 Leu Pro Gly Thr Asp Gly Trp Arg Gly Trp Gln Gly Ser GlyCys Val 50 55 60 Arg Val Ser Gly Ser Ala Pro Trp Ala Pro Gly Phe Pro PheSer Pro 65 70 75 80 Pro Cys Pro Leu Cys Gly Thr Gln Pro Arg Trp 85 90349 17 PRT Homo sapiens 349 Pro Pro Met Pro Met Pro Gly Gln Arg Glu AlaPro Gly Arg Gln Glu 1 5 10 15 Ala 350 18 PRT Homo sapiens 350 Gly ProPro Met Pro Met Pro Gly Gln Arg Glu Ala Pro Gly Arg Gln 1 5 10 15 GluAla 351 24 PRT Homo sapiens 351 Gly His Gln Cys Gln Cys Gln Gly Lys GlyArg His Arg Ala Asp Arg 1 5 10 15 Arg Pro Asp Thr Ala Gln Glu Glu 20 35223 PRT Homo sapiens 352 His Gln Cys Gln Cys Gln Gly Lys Gly Arg His ArgAla Asp Arg Arg 1 5 10 15 Pro Asp Thr Ala Gln Glu Glu 20 353 25 PRT Homosapiens 353 Gly Gly His Ser Tyr Gly Gly Gly Pro Pro Met Pro Met Pro GlyGln 1 5 10 15 Arg Glu Ala Pro Gly Arg Gln Glu Ala 20 25 354 26 PRT Homosapiens 354 Gly Gly His Ser Tyr Gly Gly Gly Gly Pro Pro Met Pro Met ProGly 1 5 10 15 Gln Arg Glu Ala Pro Gly Arg Gln Glu Ala 20 25 355 32 PRTHomo sapiens 355 Gly Gly His Ser Tyr Gly Gly Gly Gly His Gln Cys Gln CysGln Gly 1 5 10 15 Lys Gly Arg His Arg Ala Asp Arg Arg Pro Asp Thr AlaGln Glu Glu 20 25 30 356 31 PRT Homo sapiens 356 Gly Gly His Ser Tyr GlyGly Gly His Gln Cys Gln Cys Gln Gly Lys 1 5 10 15 Gly Arg His Arg AlaAsp Arg Arg Pro Asp Thr Ala Gln Glu Glu 20 25 30 357 10 PRT Homo sapiens357 Ala Pro Cys Pro Gln Ser Ser Gly Gly Gly 1 5 10 358 17 PRT Homosapiens 358 Leu Pro Ala Pro Ser Gln Ala Ala Ala Asp Glu Leu Asp Arg ArgPro 1 5 10 15 Gly 359 18 PRT Homo sapiens 359 Thr Lys Val Arg Leu IleArg Gly Ala Pro Cys Pro Gln Ser Ser Gly 1 5 10 15 Gly Gly 360 19 PRTHomo sapiens 360 Thr Lys Val Arg Leu Ile Arg Gly Gly Ala Pro Cys Pro GlnSer Ser 1 5 10 15 Gly Gly Gly 361 26 PRT Homo sapiens 361 Thr Lys ValArg Leu Ile Arg Gly Gly Leu Pro Ala Pro Ser Gln Ala 1 5 10 15 Ala AlaAsp Glu Leu Asp Arg Arg Pro Gly 20 25 362 25 PRT Homo sapiens 362 ThrLys Val Arg Leu Ile Arg Gly Leu Pro Ala Pro Ser Gln Ala Ala 1 5 10 15Ala Asp Glu Leu Asp Arg Arg Pro Gly 20 25 363 45 PRT Homo sapiens 363Cys Ser Leu Ala Lys Asp Gly Ser Thr Glu Asp Thr Val Ser Ser Leu 1 5 1015 Cys Gly Glu Glu Asp Thr Glu Asp Glu Glu Leu Glu Ala Ala Ala Ser 20 2530 His Leu Asn Lys Asp Leu Tyr Arg Glu Leu Leu Gly Gly 35 40 45 364 46PRT Homo sapiens 364 Gly Cys Ser Leu Ala Lys Asp Gly Ser Thr Glu Asp ThrVal Ser Ser 1 5 10 15 Leu Cys Gly Glu Glu Asp Thr Glu Asp Glu Glu LeuGlu Ala Ala Ala 20 25 30 Ser His Leu Asn Lys Asp Leu Tyr Arg Glu Leu LeuGly Gly 35 40 45 365 21 PRT Homo sapiens 365 Ala Ala Ala Trp Gln Lys MetAla Pro Pro Arg Thr Pro Arg Pro Ala 1 5 10 15 Cys Val Ala Arg Arg 20 36654 PRT Homo sapiens 366 Glu Asn Ser Arg Pro Lys Arg Gly Gly Cys Ser LeuAla Lys Asp Gly 1 5 10 15 Ser Thr Glu Asp Thr Val Ser Ser Leu Cys GlyGlu Glu Asp Thr Glu 20 25 30 Asp Glu Glu Leu Glu Ala Ala Ala Ser His LeuAsn Lys Asp Leu Tyr 35 40 45 Arg Glu Leu Leu Gly Gly 50 367 55 PRT Homosapiens 367 Glu Asn Ser Arg Pro Lys Arg Gly Gly Gly Cys Ser Leu Ala LysAsp 1 5 10 15 Gly Ser Thr Glu Asp Thr Val Ser Ser Leu Cys Gly Glu GluAsp Thr 20 25 30 Glu Asp Glu Glu Leu Glu Ala Ala Ala Ser His Leu Asn LysAsp Leu 35 40 45 Tyr Arg Glu Leu Leu Gly Gly 50 55 368 30 PRT Homosapiens 368 Glu Asn Ser Arg Pro Lys Arg Gly Gly Ala Ala Ala Trp Gln LysMet 1 5 10 15 Ala Pro Pro Arg Thr Pro Arg Pro Ala Cys Val Ala Arg Arg 2025 30 369 29 PRT Homo sapiens 369 Glu Asn Ser Arg Pro Lys Arg Gly AlaAla Ala Trp Gln Lys Met Ala 1 5 10 15 Pro Pro Arg Thr Pro Arg Pro AlaCys Val Ala Arg Arg 20 25 370 10 PRT Homo sapiens 370 His Cys Val LeuAla Ala Ser Gly Ala Ser 1 5 10 371 11 PRT Homo sapiens 371 Gly His CysVal Leu Ala Ala Ser Gly Ala Ser 1 5 10 372 28 PRT Homo sapiens 372 GlyThr Ala Ser Ser Arg Pro Leu Gly Leu Pro Lys Pro His Leu His 1 5 10 15Arg Pro Val Pro Ile Arg His Pro Ser Cys Pro Lys 20 25 373 27 PRT Homosapiens 373 Thr Ala Ser Ser Arg Pro Leu Gly Leu Pro Lys Pro His Leu HisArg 1 5 10 15 Pro Val Pro Ile Arg His Pro Ser Cys Pro Lys 20 25 374 18PRT Homo sapiens 374 Ala Gly Thr Leu Gln Leu Gly Gly His Cys Val Leu AlaAla Ser Gly 1 5 10 15 Ala Ser 375 19 PRT Homo sapiens 375 Ala Gly ThrLeu Gln Leu Gly Gly Gly His Cys Val Leu Ala Ala Ser 1 5 10 15 Gly AlaSer 376 35 PRT Homo sapiens 376 Ala Gly Thr Leu Gln Leu Gly Gly Thr AlaSer Ser Arg Pro Leu Gly 1 5 10 15 Leu Pro Lys Pro His Leu His Arg ProVal Pro Ile Arg His Pro Ser 20 25 30 Cys Pro Lys 35 377 36 PRT Homosapiens 377 Ala Gly Thr Leu Gln Leu Gly Gly Gly Thr Ala Ser Ser Arg ProLeu 1 5 10 15 Gly Leu Pro Lys Pro His Leu His Arg Pro Val Pro Ile ArgHis Pro 20 25 30 Ser Cys Pro Lys 35 378 9 PRT Homo sapiens 378 Arg ArgThr Pro Ser Thr Glu Lys Arg 1 5 379 10 PRT Homo sapiens 379 Arg Arg ThrPro Ser Thr Glu Lys Lys Arg 1 5 10 380 14 PRT Homo sapiens 380 Arg ArgThr Pro Ser Thr Glu Lys Lys Gly Arg Ser Glu Cys 1 5 10 381 13 PRT Homosapiens 381 Arg Arg Thr Pro Ser Thr Glu Lys Gly Arg Ser Glu Cys 1 5 10382 46 PRT Homo sapiens 382 Ser Thr Thr Lys Cys Gln Ser Gly Thr Ala GluThr Tyr Asn Ser Trp 1 5 10 15 Lys Val Lys Asn Leu Gln Leu Glu Pro ArgArg Val Thr Ser Gln Met 20 25 30 Asn Arg Gln Val Lys Asp Met Thr Ala IleLeu Ser Gln Ser 35 40 45 383 17 PRT Homo sapiens 383 Val Gln Pro Asn AlaSer Gln Ala Gln Gln Lys Pro Thr Thr His Gly 1 5 10 15 Arg 384 54 PRTHomo sapiens 384 Ser Ser Glu Glu Ile Lys Lys Lys Ser Thr Thr Lys Cys GlnSer Gly 1 5 10 15 Thr Ala Glu Thr Tyr Asn Ser Trp Lys Val Lys Asn LeuGln Leu Glu 20 25 30 Pro Arg Arg Val Thr Ser Gln Met Asn Arg Gln Val LysAsp Met Thr 35 40 45 Ala Ile Leu Ser Gln Ser 50 385 55 PRT Homo sapiens385 Ser Ser Glu Glu Ile Lys Lys Lys Lys Ser Thr Thr Lys Cys Gln Ser 1 510 15 Gly Thr Ala Glu Thr Tyr Asn Ser Trp Lys Val Lys Asn Leu Gln Leu 2025 30 Glu Pro Arg Arg Val Thr Ser Gln Met Asn Arg Gln Val Lys Asp Met 3540 45 Thr Ala Ile Leu Ser Gln Ser 50 55 386 26 PRT Homo sapiens 386 SerSer Glu Glu Ile Lys Lys Lys Lys Val Gln Pro Asn Ala Ser Gln 1 5 10 15Ala Gln Gln Lys Pro Thr Thr His Gly Arg 20 25 387 25 PRT Homo sapiens387 Ser Ser Glu Glu Ile Lys Lys Lys Val Gln Pro Asn Ala Ser Gln Ala 1 510 15 Gln Gln Lys Pro Thr Thr His Gly Arg 20 25 388 9 PRT Homo sapiens388 Asn Arg Gly Trp Val Gly Ala Gly Glu 1 5 389 4 PRT Homo sapiens 389Ile Glu Ala Gly 1 390 17 PRT Homo sapiens 390 Val His Asn Tyr Cys AsnMet Lys Asn Arg Gly Trp Val Gly Ala Gly 1 5 10 15 Glu 391 18 PRT Homosapiens 391 Val His Asn Tyr Cys Asn Met Lys Lys Asn Arg Gly Trp Val GlyAla 1 5 10 15 Gly Glu 392 13 PRT Homo sapiens 392 Val His Asn Tyr CysAsn Met Lys Lys Ile Glu Ala Gly 1 5 10 393 12 PRT Homo sapiens 393 ValHis Asn Tyr Cys Asn Met Lys Ile Glu Ala Gly 1 5 10 394 25 PRT Homosapiens 394 Gln Leu Arg Cys Trp Asn Thr Trp Ala Lys Met Phe Phe Met ValPhe 1 5 10 15 Leu Ile Ile Trp Gln Asn Thr Met Phe 20 25 395 33 PRT Homosapiens 395 Val Lys Lys Asp Asn His Lys Lys Gln Leu Arg Cys Trp Asn ThrTrp 1 5 10 15 Ala Lys Met Phe Phe Met Val Phe Leu Ile Ile Trp Gln AsnThr Met 20 25 30 Phe 396 34 PRT Homo sapiens 396 Val Lys Lys Asp Asn HisLys Lys Lys Gln Leu Arg Cys Trp Asn Thr 1 5 10 15 Trp Ala Lys Met PhePhe Met Val Phe Leu Ile Ile Trp Gln Asn Thr 20 25 30 Met Phe 397 11 PRTHomo sapiens 397 Val Lys Lys Asp Asn His Lys Lys Lys Asn Ser 1 5 10 39810 PRT Homo sapiens 398 Val Lys Lys Asp Asn His Lys Lys Asn Ser 1 5 10399 35 PRT Homo sapiens 399 Gly Ala Glu Glu Ser Gly Pro Phe Asn Arg GlnVal Gln Leu Lys Val 1 5 10 15 His Ala Ser Gly Met Gly Arg His Leu TrpAsn Cys Pro Ala Phe Trp 20 25 30 Ser Glu Val 35 400 10 PRT Homo sapiens400 His Pro Ser Pro Pro Pro Glu Lys Arg Ser 1 5 10 401 11 PRT Homosapiens 401 His Pro Ser Pro Pro Pro Glu Lys Lys Arg Ser 1 5 10 402 44PRT Homo sapiens 402 His Pro Ser Pro Pro Pro Glu Lys Lys Gly Ala Glu GluSer Gly Pro 1 5 10 15 Phe Asn Arg Gln Val Gln Leu Lys Val His Ala SerGly Met Gly Arg 20 25 30 His Leu Trp Asn Cys Pro Ala Phe Trp Ser Glu Val35 40 403 43 PRT Homo sapiens 403 His Pro Ser Pro Pro Pro Glu Lys GlyAla Glu Glu Ser Gly Pro Phe 1 5 10 15 Asn Arg Gln Val Gln Leu Lys ValHis Ala Ser Gly Met Gly Arg His 20 25 30 Leu Trp Asn Cys Pro Ala Phe TrpSer Glu Val 35 40 404 39 PRT Homo sapiens 404 Met Gln Val Leu Ser LysThr His Met Asn Leu Phe Pro Gln Val Leu 1 5 10 15 Leu Gln Met Phe LeuArg Gly Leu Lys Arg Leu Leu Gln Asp Leu Glu 20 25 30 Lys Ser Lys Lys ArgLys Leu 35 405 8 PRT Homo sapiens 405 Arg Cys Lys Ser Ala Arg Leu Ile 15 406 48 PRT Homo sapiens 406 Val Gln Thr Gln Pro Ala Ile Lys Lys MetGln Val Leu Ser Lys Thr 1 5 10 15 His Met Asn Leu Phe Pro Gln Val LeuLeu Gln Met Phe Leu Arg Gly 20 25 30 Leu Lys Arg Leu Leu Gln Asp Leu GluLys Ser Lys Lys Arg Lys Leu 35 40 45 407 49 PRT Homo sapiens 407 Val GlnThr Gln Pro Ala Ile Lys Lys Lys Met Gln Val Leu Ser Lys 1 5 10 15 ThrHis Met Asn Leu Phe Pro Gln Val Leu Leu Gln Met Phe Leu Arg 20 25 30 GlyLeu Lys Arg Leu Leu Gln Asp Leu Glu Lys Ser Lys Lys Arg Lys 35 40 45 Leu408 17 PRT Homo sapiens 408 Val Gln Thr Gln Pro Ala Ile Lys Lys Arg CysLys Ser Ala Arg Leu 1 5 10 15 Ile 409 16 PRT Homo sapiens 409 Val GlnThr Gln Pro Ala Ile Lys Arg Cys Lys Ser Ala Arg Leu Ile 1 5 10 15 410 11PRT Homo sapiens 410 Ala Arg Ser Gly Lys Lys Gln Lys Arg Lys Leu 1 5 10411 12 PRT Homo sapiens 411 Ala Arg Ser Gly Lys Lys Gln Lys Lys Arg LysLeu 1 5 10 412 13 PRT Homo sapiens 412 Ala Arg Ser Gly Lys Lys Gln LysLys Glu Asn Ser Phe 1 5 10 413 12 PRT Homo sapiens 413 Ala Arg Ser GlyLys Lys Gln Lys Glu Asn Ser Phe 1 5 10 414 14 PRT Homo sapiens 414 LysAla Ser Ala Arg Ser Gly Lys Ser Lys Lys Arg Lys Leu 1 5 10 415 15 PRTHomo sapiens 415 Lys Ala Ser Ala Arg Ser Gly Lys Lys Ser Lys Lys Arg LysLeu 1 5 10 15 416 16 PRT Homo sapiens 416 Lys Ala Ser Ala Arg Ser GlyLys Lys Ala Lys Lys Glu Asn Ser Phe 1 5 10 15 417 15 PRT Homo sapiens417 Lys Ala Ser Ala Arg Ser Gly Lys Ala Lys Lys Glu Asn Ser Phe 1 5 1015 418 15 PRT Homo sapiens 418 His Leu Asn Lys Gly Arg Arg Leu Gly AspLys Ile Arg Ala Thr 1 5 10 15 419 23 PRT Homo sapiens 419 Val Thr SerGly Thr Pro Phe Phe His Leu Asn Lys Gly Arg Arg Leu 1 5 10 15 Gly AspLys Ile Arg Ala Thr 20 420 24 PRT Homo sapiens 420 Val Thr Ser Gly ThrPro Phe Phe Phe His Leu Asn Lys Gly Arg Arg 1 5 10 15 Leu Gly Asp LysIle Arg Ala Thr 20 421 10 PRT Homo sapiens 421 Val Thr Ser Gly Thr ProPhe Phe Phe Ile 1 5 10 422 9 PRT Homo sapiens 422 Val Thr Ser Gly ThrPro Phe Phe Ile 1 5 423 51 PRT Homo sapiens 423 Val Thr Leu Leu Tyr ValAsn Thr Val Thr Leu Ala Pro Asn Val Asn 1 5 10 15 Met Glu Ser Ser ArgAsn Ala His Ser Pro Ala Thr Pro Ser Ala Lys 20 25 30 Arg Lys Asp Pro AspLeu Thr Trp Gly Gly Phe Val Phe Phe Phe Cys 35 40 45 Gln Phe His 50 42460 PRT Homo sapiens 424 Lys Cys Arg Cys Lys Pro Asn Phe Phe Val Thr LeuLeu Tyr Val Asn 1 5 10 15 Thr Val Thr Leu Ala Pro Asn Val Asn Met GluSer Ser Arg Asn Ala 20 25 30 His Ser Pro Ala Thr Pro Ser Ala Lys Arg LysAsp Pro Asp Leu Thr 35 40 45 Trp Gly Gly Phe Val Phe Phe Phe Cys Gln PheHis 50 55 60 425 61 PRT Homo sapiens 425 Lys Cys Arg Cys Lys Pro Asn PhePhe Phe Val Thr Leu Leu Tyr Val 1 5 10 15 Asn Thr Val Thr Leu Ala ProAsn Val Asn Met Glu Ser Ser Arg Asn 20 25 30 Ala His Ser Pro Ala Thr ProSer Ala Lys Arg Lys Asp Pro Asp Leu 35 40 45 Thr Trp Gly Gly Phe Val PhePhe Phe Cys Gln Phe His 50 55 60 426 10 PRT Homo sapiens 426 Lys Cys ArgCys Lys Pro Asn Phe Phe Leu 1 5 10 427 9 PRT Homo sapiens 427 Lys CysArg Cys Lys Pro Asn Phe Leu 1 5 428 9 PRT Homo sapiens 428 Ser Leu ValArg Leu Ser Ser Cys Val 1 5 429 14 PRT Homo sapiens 429 Leu Val Lys LysLeu Lys Glu Lys Lys Met Asn Trp Ile Leu 1 5 10 430 15 PRT Homo sapiens430 Leu Val Lys Lys Leu Lys Glu Lys Lys Lys Met Asn Trp Ile Leu 1 5 1015 431 10 PRT Homo sapiens 431 Leu Val Lys Lys Leu Lys Glu Lys Lys Arg 15 10 432 9 PRT Homo sapiens 432 Leu Val Lys Lys Leu Lys Glu Lys Arg 1 5433 9 PRT Homo sapiens 433 Ala Ala Ile Val Lys Asp Cys Cys Arg 1 5 43411 PRT Homo sapiens 434 Ser Gln Pro Ala Ser Ile Leu Gly Arg Lys Leu 1 510 435 12 PRT Homo sapiens 435 Ser Gln Pro Ala Ser Ile Leu Gly Lys ArgLys Leu 1 5 10 436 18 PRT Homo sapiens 436 Ser Gln Pro Ala Ser Ile LeuGly Lys Ala Ala Ile Val Lys Asp Cys 1 5 10 15 Cys Arg 437 17 PRT Homosapiens 437 Ser Gln Pro Ala Ser Ile Leu Gly Ala Ala Ile Val Lys Asp CysCys 1 5 10 15 Arg 438 18 PRT Homo sapiens 438 Lys Ser Leu Val Arg LeuSer Ser Cys Val Pro Val Ala Leu Met Ser 1 5 10 15 Ala Met 439 9 PRT Homosapiens 439 Arg Leu Ser Ser Cys Val Pro Val Ala 1 5 440 9 PRT Homosapiens 440 Val Arg Leu Ser Ser Cys Val Pro Val 1 5 441 9 PRT Homosapiens 441 Leu Val Arg Leu Ser Ser Cys Val Pro 1 5 442 9 PRT Homosapiens 442 Ser Cys Val Pro Val Ala Leu Met Ser 1 5 443 9 PRT Homosapiens 443 Ser Ser Cys Val Pro Val Ala Leu Met 1 5 444 9 PRT Homosapiens 444 Leu Ser Ser Cys Val Pro Val Ala Leu 1 5 445 9 PRT Homosapiens 445 Val Pro Val Ala Leu Met Ser Ala Met 1 5 446 9 PRT Homosapiens 446 Cys Val Pro Val Ala Leu Met Ser Ala 1 5 447 9 PRT Homosapiens 447 Lys Lys Lys Ser Leu Val Arg Leu Ser 1 5 448 9 PRT Homosapiens 448 Glu Lys Lys Lys Ser Leu Val Arg Leu 1 5 449 9 PRT Homosapiens 449 Lys Glu Lys Lys Lys Ser Leu Val Arg 1 5 450 9 PRT Homosapiens 450 Met Lys Glu Lys Lys Lys Ser Leu Val 1 5 451 9 PRT Homosapiens 451 Ile Met Lys Glu Lys Lys Lys Ser Leu 1 5 452 9 PRT Homosapiens 452 Lys Cys Ile Met Lys Glu Lys Lys Ala 1 5 453 9 PRT Homosapiens 453 Cys Ile Met Lys Glu Lys Lys Ala Trp 1 5 454 9 PRT Homosapiens 454 Cys Ile Met Lys Glu Lys Lys Lys Ala 1 5 455 9 PRT Homosapiens 455 Ile Met Lys Glu Lys Lys Lys Ala Trp 1 5 456 13 PRT Homosapiens 456 His Pro Ser Trp Pro Trp Thr Arg Cys Leu Arg Met Arg 1 5 10457 14 PRT Homo sapiens 457 Arg His Pro Ser Trp Pro Trp Thr Arg Cys LeuArg Met Arg 1 5 10 458 16 PRT Homo sapiens 458 Gly Ala Ser Gly Cys ValHis Gln Glu Ala Glu Arg Val Ser Gln Ala 1 5 10 15 459 20 PRT Homosapiens 459 Asn Thr Trp Ala Lys Met Phe Phe Met Val Phe Leu Ile Ile TrpGln 1 5 10 15 Asn Thr Met Phe 20

What is claimed is:
 1. An isolated peptide selected from the groupconsisting of Seq ID No. 17 and Seq ID No.
 428. 2. An isolated peptideconsisting of Seq ID No.
 17. 3. An isolated peptide consisting of Seq IDNo.
 428. 4. A composition comprising a peptide according to claim 1 anda carrier or diluent therefor.
 5. A composition comprising a peptideaccording to claim 2 and a carrier or diluent therefor.
 6. A compositioncomprising a peptide according to claim 3 and a carrier or diluenttherefor.
 7. A method of stimulating the proliferation of human T cells,comprising the steps of: i) obtaining T cells from a human cancerpatient and ii) contacting the T cells obtained in step i) with apeptide selected from the group consisting of Seq ID No. 17 and Seq IDNo. 428, said peptide being capable of inducing T cell proliferation,either in its full length form or after processing by anantigen-presenting cell.
 8. The method of claim 7, wherein the peptideused in step ii) is Seq ID No.
 17. 9. The method of claim 7, wherein thepeptide used in step ii) is Seq ID No. 428.